Agent for inducing angiogenesis

Abstract

The present invention relates to an agent capable of inducing angiogenesis. The disclosure also relates to the treatment of diseases, such as cardiovascular diseases, using said agents.

Description

Technical Field

[0001] The present invention relates to agents capable of inducing angiogenesis. The present disclosure also relates to using the agents to treat diseases, such as cardiovascular diseases. Background Art

[0002] Cardiovascular disease (CVD) is a class of diseases involving the heart or blood vessels. CVD includes coronary artery disease (CAD), such as angina and myocardial infarction (commonly known as a heart attack). Other CVD include stroke, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, arrhythmias, congenital heart disease, valvular heart disease, myocarditis, aortic aneurysm, peripheral arterial disease, thromboembolic disease and venous thrombosis.

[0003] The underlying mechanisms vary depending on the disease. Dietary risk factors are estimated to be associated with 53% of CVD deaths. Coronary artery disease, stroke, and peripheral artery disease involve atherosclerosis. This can be caused, among other things, by high blood pressure, smoking, diabetes, lack of exercise, obesity, high blood cholesterol, poor diet, excessive alcohol consumption, and lack of sleep. It is estimated that high blood pressure accounts for about 13% of CVD deaths, while smoking accounts for 9%, diabetes accounts for 6%, lack of exercise accounts for 6%, and obesity accounts for 5%. Rheumatic heart disease can follow untreated strep throat. Summary of the invention

[0004] The inventors of the present disclosure have identified peptides that are capable of inducing angiogenesis. Therefore, the peptides are promising candidates for treating various diseases or conditions associated with reduced angiogenesis, including cardiovascular diseases.

[0005] One aspect of the present disclosure provides a medicament comprising:

[0006] a) a peptide selected from the group consisting of:

[0007] (i) a peptide comprising or consisting of an amino acid sequence of the following general formula:

[0008] X5X6SX7X8YGLR (SEQ ID NO: 1)

[0009] in:

[0010] X5 is D or G;

[0011] X6 is I or G;

[0012] X7 is V or L;

[0013] X8 is V or A;

[0014] (ii) a peptide comprising or consisting of an amino acid sequence of the following general formula:

[0015] X 14 LX 15 YGIK (SEQ ID NO: 105)

[0016] in:

[0017] X 14 is E or G;

[0018] X 15 is S or T;

[0019] (iii) a peptide comprising or consisting of an amino acid sequence selected from the group consisting of:

[0020] VDTYDGDISVVYGL(SEQ ID NO:34),

[0021] VDTYDGDISVVYG(SEQ ID NO:35),

[0022] VDTYDGDISVVY (SEQ ID NO: 36),

[0023] VDTYDGDISVV (SEQ ID NO: 37),

[0024] VDTYDGDISV (SEQ ID NO: 38),

[0025] VDTYDGDIS (SEQ ID NO: 39),

[0026] VDTYDGRGDSVVYGLR(SEQ ID NO:40),

[0027] VDVPNGDISLAYGL(SEQ ID NO:41),

[0028] VDVPNGDISLAYG(SEQ ID NO:42),

[0029] VDVPNGDISLA (SEQ ID NO: 43),

[0030] VDVPNGDIS (SEQ ID NO: 44),

[0031] GDPNDGRGDSVVYGLR(SEQ ID NO:45),

[0032] LDGLVRAYDNISPVG(SEQ ID NO:46),

[0033] GDPNGDISVVYGLR (SEQ ID NO: 47)

[0034] VDVPNGDISLAYRLR(SEQ ID NO:48),

[0035] VDVPEGDISLAYRLR(SEQ ID NO:49),

[0036] V(beta-D)TYDGDISVVYGLR(SEQ ID NO:50),

[0037] VDTY(beta-D)GDISVVYGLR(SEQ ID NO:51),

[0038] VDTYDG(beta-D)ISVVYGLR(SEQ ID NO:52);

[0039] CLAEIDSC (circular) (SEQ ID NO: 130),

[0040] CFKPLAEIDSIECSYGIK(cyclic) (SEQ ID NO: 131),

[0041] cyclic CFKPLAEIDSIEC (SEQ ID NO: 132),

[0042] KPLAEIDSIELSYGI(SEQ ID NO:133),

[0043] KPLAEIDSIELSYG(SEQ ID NO:134),

[0044] KPLAEIDSIELSY(SEQ ID NO:135),

[0045] KPLAEIDSIELS(SEQ ID NO:136),

[0046] KPLAEIDSIEL (SEQ ID NO: 137), and

[0047] KPLAEIDSIE (SEQ ID NO: 138);

[0048] b) a polynucleotide which, when expressed, encodes the peptide of a);

[0049] c) a vector comprising the polynucleotide of b); or

[0050] d) a cell comprising the polynucleotide of b) or the vector of c),

[0051] It is used for treating and / or preventing a disease or condition associated with reduced or impaired angiogenesis in a subject.

[0052] In one aspect, the invention relates to a method for treating or preventing a disease or disorder in a subject, wherein the disease or disorder is selected from the group consisting of:

[0053] i. Diseases of the circulatory system,

[0054] ii. Damage caused by external factors,

[0055] iii. Diseases of the immune system,

[0056] iv. Diseases of the nervous system, and

[0057] v. Diseases of the musculoskeletal system or connective tissue,

[0058] The method comprises administering to a subject in need thereof a therapeutically effective amount of an agent as described herein.

[0059] In one aspect, the invention relates to the use of an agent as defined herein for the manufacture of a medicament for the treatment or prevention of a disease or condition selected from the group consisting of:

[0060] i. Diseases of the circulatory system,

[0061] ii. Damage caused by external factors,

[0062] iii. Diseases of the immune system,

[0063] iv. Diseases of the nervous system, and

[0064] v. Diseases of the musculoskeletal system or connective tissue.

[0065] In one aspect, the invention relates to a medicament as defined herein for use in improving post-operative vascularization in a subject.

[0066] In one aspect, the invention relates to a method for inducing angiogenesis, said method comprising administering to a subject an agent as defined herein.

[0067] In one aspect, the invention relates to an implant comprising a peptide as defined herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 : FOL26 stimulates endothelial cell and vascular smooth muscle cell proliferation. Human umbilical cord endothelial cells (A) and human coronary artery smooth muscle cells (B) were treated with FOL26 at concentrations of 10 nM, 100 nM and 1000 nM, and DNA synthesis was analyzed by measuring the uptake of BrdU. The OD (450 nm) of the cell lines treated with FOL 26 increased compared to the control.

[0069] Figure 2: FOL26 enhances endothelial cell tube formation and expression of PECAM-1. Human umbilical cord endothelial cells were treated with FOL26 at concentrations of 10nM, 100nM and 1000nM, and endothelial tube formation and gene expression of PECAM-1 (CD31) were analyzed. Compared to the control, FOL26 increased tube formation. The expression of PECAM-1 was increased for 100nM and 1000nM FOL26.

[0070] Figure 3 : FOL26 inhibits apoptosis of endothelial cells and arterial smooth muscle cells. Cultured human umbilical cord endothelial cells and coronary artery smooth muscle cells were exposed to soluble Fas ligand (sFasL) to induce apoptosis which was subsequently evaluated by determining the activation of caspase 3 and 7. Cells were also treated with FOL26 at concentrations of 10 nM, 100 nM, and 1000 nM to determine the effect on apoptosis activated by sFasL. FOL26 was able to reverse sFasL-induced apoptosis, reaching the highest extent at a concentration of 100 nM.

[0071] Figure 4 : FOL26 affects gene expression of VEGF and VEGF receptor family in endothelial cells. Human umbilical cord endothelial cells were treated with FOL 26 at concentrations of 10 nM, 100 nM and 1000 nM, and the expression of genes encoding c-Met, neuropilin-1 (NRP-1), VEGF-A and VEGF receptor-2 (VEGFR-2) was determined by polymerase chain reaction (PCR). FOL026 reduced c-Met expression, reduced NRP-1 expression at the lowest dose, however, induced NRP-1 expression at doses of 100 nM and 1000 nM. FOL026 had no effect on VEGF-A expression, however, at 10 nM, it reduced the expression of VEGFR-2 levels, and at 1000 nM, it induced the expression of VEGFR-2 levels.

[0072] Figure 5 :FOL26 affects gene expression of cytokines and matrix metalloproteinases in endothelial cells. Human umbilical cord endothelial cells were treated with FOL 26 at concentrations of 10nM, 100nM and 1000nM, and the expression of genes encoding TNF-α, IL-6, MMP2 and MMP3 was determined by polymerase chain reaction (PCR). TNF-α is a strong proinflammatory cytokine, while MMP2 is required for smooth muscle cell proliferation and migration activation. FOL026 reduced TNF-α expression at 10nM and 100nM doses, had no effect on IL-6 or MMP3 expression, however, induced MMP2 expression at 200nM and 1000nM doses.

[0073] Figure 6: FOL26 affects gene expression of VEGF and VEGF receptor family in arterial smooth muscle cells. Human coronary artery smooth muscle cells were treated with FOL26 at concentrations of 10 nM, 100 nM and 1000 nM, and the expression of genes encoding c-Met, neuropilin-1 (NRP-1), VEGF-A and VEGF receptor-2 (VEGFR-2) was determined by polymerase chain reaction (PCR). FOL026 reduced c-MET expression at 10 nM and 1000 nM doses, and reduced NRP-1 expression at 10, 100 and 1000 nM doses. FOL026 induced VEGF-A expression at 10, 100 and 1000 nM doses, and only for FOL026 100 nM dose.

[0074] Figure 7 :FOL26 affects gene expression of cytokines and matrix metalloproteinases in arterial smooth muscle cells. Human coronary artery smooth muscle cells were treated with FOL 26 at concentrations of 10nM, 100nM and 1000nM, and the expression of genes encoding TNF-α, IL-6, MMP2 and MMP3 was determined by polymerase chain reaction (PCR). TNF-α is a strong proinflammatory cytokine, while MMP2 is required for smooth muscle cell proliferation and migration activation. FOL026 100 and 1000nM induced TNF-α, IL-6 and MMP3 expression, and in addition, FOL026 induced MMP2 expression at 10, 100 and 1000nM doses.

[0075] Figure 8 : FOL26 stimulation of endothelial cell proliferation is NRP-1 dependent. Human umbilical cord endothelial cells were first treated with scrambled non-coding siRNA (NC) or siRNA against NRP-1, then treated with FOL26 at concentrations of 10 nM, 100 nM and 1000 nM, and DNA synthesis was analyzed by measuring the uptake of BrdU. The increase in OD (450 nm) of the FOL 26 treated cell lines compared to the control showed that FOL26-induced angiogenesis may be NRP-1 dependent, as a decrease was observed for FOL26 10 and 100 nM.

[0076] Fig. 9 : Human umbilical cord endothelial cells were treated with scrambled noncoding siRNA (NC) or siRNA against NRP-1 at concentrations of 1 nM and 5 nM, and the expression values ​​of NRP-1 and glyceraldehyde phosphate dehydrogenase (GAPDH) mRNA were evaluated, the latter used as an internal control to normalize the data.

[0077] Fig.10: FOL26 enhances endothelial cell tubes in an NRP-1 specific manner. Human umbilical cord endothelial cells were first treated with scrambled noncoding siRNA (NC) or siRNA for NRP-1, followed by treatment with FOL26 at concentrations of 10nM, 100nM, and 1000nM, and endothelial tube formation and total primary segments were measured using ImageJ. Gene expression of PECAM-1 (CD31) was analyzed. FOL26 increased tube formation in an NRP-1 dependent manner compared to controls. Scale bar: 150μm.

[0078] Fig.11 : FOL56 stimulates endothelial cell and vascular smooth muscle cell proliferation. Human umbilical cord endothelial cells (A) and human coronary artery smooth muscle cells (B) were treated with FOL 56 at concentrations of 10 nM, 100 nM and 1000 nM, and DNA synthesis was analyzed by measuring the uptake of BrdU. Compared with the control, FOL56 increased the proliferation of both HUVEC and HCASMC at all concentrations.

[0079] Fig.12 : FOL56 enhances endothelial cell tube formation and expression of PECAM-1. Human umbilical cord endothelial cells were treated with FOL 56 at concentrations of 10 nM, 100 nM and 1000 nM, and the gene expression of endothelial tube formation and PECAM-1 (CD31) was analyzed. Compared with the control, FOL56 increased tube formation at all concentrations and also increased the expression of PECAM-1.

[0080] Fig.13 : FOL56 inhibits apoptosis of endothelial cells and arterial smooth muscle cells. Cultured human umbilical cord endothelial cells and coronary artery smooth muscle cells were exposed to soluble Fas ligand (sFasL) to induce apoptosis which was subsequently evaluated by determining the activation of caspase 3 and 7. Cells were also treated with FOL 56 at concentrations of 10 nM, 100 nM, and 1000 nM to determine the effect on apoptosis activated by sFasL. FOL56 was able to inhibit or tend to inhibit apoptosis of both HUVEC and HCASMC.

[0081] Fig.14 : FOL56 affects the gene expression of VEGF and VEGF receptor family in endothelial cells. Human umbilical cord endothelial cells were treated with FOL 56 at concentrations of 10 nM, 100 nM and 1000 nM, and the expression of genes encoding c-Met, neuropilin-1 (NRP-1), VEGF-A and VEGF receptor-2 (VEGFR-2) was determined by polymerase chain reaction (PCR).

[0082] Fig.15:FOL56 affects the gene expression of cytokines and matrix metalloproteinases in endothelial cells. Human umbilical cord endothelial cells were treated with FOL 56 at concentrations of 10nM, 100nM and 1000nM, and the expression of genes encoding TNF-α, IL-6, MMP2 and MMP3 was determined by polymerase chain reaction (PCR). TNF-α is a strong proinflammatory cytokine, while MMP2 is essential for the activation of smooth muscle cell proliferation and migration.

[0083] Fig.16 : FOL56 affects the gene expression of VEGF and VEGF receptor family in arterial smooth muscle cells. Human coronary artery smooth muscle cells were treated with FOL 56 at concentrations of 10 nM, 100 nM and 1000 nM, and the expression of genes encoding c-Met, neuropilin-1 (NRP-1), VEGF-A and VEGF receptor-2 (VEGFR-2) was determined by polymerase chain reaction (PCR).

[0084] Fig.17 :FOL56 affects the gene expression of cytokines and matrix metalloproteinases in arterial smooth muscle cells. Human coronary artery smooth muscle cells were treated with FOL 56 at concentrations of 10nM, 100nM and 1000nM, and the expression of genes encoding TNF-α, IL-6, MMP2 and MMP3 was determined by polymerase chain reaction (PCR). TNF-α is a strong proinflammatory cytokine, while MMP2 is essential for the activation of smooth muscle cell proliferation and migration.

[0085] Fig.18 Effect of FOL-026 peptide on endothelial cell function and gene expression. The effects of FOL-026 peptide on human umbilical vascular endothelial cell (HUVEC) proliferation (A) and apoptosis induced by hypoxic conditions (B) were determined by BrdU uptake (n=8-9 / group) and active caspase-3 / -7 (n=7-10 / group), respectively. ROS levels activated by 50ug / ml oxidized low-density lipoprotein (oxLDL) for 2 hours in cells pre-incubated with FOL-026 peptide were evaluated using H2O2 measurement (n=4-8 / group) (C).

[0086] Fig.19 Representative images of endothelial cell migration into in vitro scratches are shown (A), and wound closure rates in HUVECs stimulated with increasing concentrations of FOL-026 peptide were quantified by image J software (B) (n=8-9 / group). Scale bar=150 um.

[0087] Fig. 20Effect of FOL-026 peptide on angiogenesis in vitro and in vivo. Representative images of tube formation in HUVECs treated with FOL-026 peptide (A). Quantitative measurements of total length (B), total main segment length (C), total branch length (D), and total segment length (E) were performed to assess in vitro angiogenesis (n=7 / group for BE).

[0088] Fig.21 Quantification of vascular density evaluated by CD31+ positive area (A) (n=13 / group). Western blot analysis of phosphorylated AKT (pAKT-T308), AKT, phosphorylated ERK1 / 2 (p-ERK1 / 2), and ERK1 / 2 in endothelial cells stimulated with FOL-26 peptide for 48 hours (B). Quantification of phosphorylation intensity was normalized to the total expression of each (C and D, n=3 / group).

[0089] Fig. 22 Effect of NRP-1 knockdown on endothelial cell function induced by FOL-026 peptide. The efficiency of small interfering RNA transfection in HUVEC for 48 hours was confirmed by qRT-PCR (n=4) (A). The effect of FOL-026 peptide stimulation on cell proliferation (B) and apoptosis (C) under 0.1% oxygen in HUVECs transfected with siRNA-NC or siNRP-1 was assessed by BrdU incorporation (n=4-7 / group) and active caspase-3 / -7 (n=4-7 / group).

[0090] Fig.23 Representative images of endothelial cells at 0 and 5 hours after scratching are shown in (A). Wound closure rate of siRNA-NC / siNRP-1 transfected HUVECs stimulated with increasing concentrations of FOL-026 peptide was quantified by image J software (B) (n=9-12 / group). Scale bar=150 um.

[0091] Fig.24 .Effect of NRP-1 knockdown on tube formation induced by FOL-026 peptide. Tube formation (A), total length (B), total main segment length (C), total branch length (D), and total segment length (E) in siRNA-NC or siNRP-1 groups with increasing doses of FOL-026 peptide treatment were calculated using the Angiogenesis Analyzer plugin ImageJ (n=7-12 / group). Scale bar=150um.

[0092] Fig.25Effect of FOL-026 peptide on smooth muscle cell function. The effect of FOL-026 peptide treatment on smooth muscle cell proliferation (A) and apoptosis induced by hypoxic conditions (B) was evaluated by BrdU uptake (n=10 / group) and active caspase-3 / -7 (n=6-8 / group), respectively. H2O2 measurement of smooth muscle cells pre-incubated with FOL-26 peptide after 2 hours of stimulation with 50ug / ml oxidized low-density lipoprotein (oxLDL) (C) (n=6-7 / group).

[0093] Fig.26 Representative images of in vitro scratch wound assay are shown in (A), and wound healing ability in human coronary artery smooth muscle cells (HCASMC) treated with FOL-026 peptide was measured by image J software (B) (n=10 / group). Scale bar=150 um.

[0094] Fig. 27 Effect of NRP-1 knockdown on smooth muscle cell function induced by FOL-026 peptide. qRT-PCR analysis of NRP-1 mRNA expression in HCASMC transfected with small interfering RNA for 48 hours (n=4) (A). Evaluation of BrdU incorporation (B) (n=10-11) and caspase-3 / -7 activation (C) (n=3-10) in siRNA-NC / siNRP-1 transfected HUVEC treated with indicated concentrations of FOL-026 peptide.

[0095] Fig.28 Representative images of smooth muscle cells at 0 and 5 hours after scratching are shown in (A). The wound closure rate of HCASMCs in siRNA-NC and siNRP-1 groups stimulated with increasing concentrations of FOL-026 peptide was quantified by image J software (B) (n=9-12 / group). Scale bar=150 um.

[0096] Fig.29 Effect of FOL-005 peptide on endothelial and smooth muscle cell proliferation and wound healing ability. Endothelial cell proliferation was evaluated by BrdU uptake in human umbilical vascular endothelial cells (HUVECs) stimulated with increasing concentrations of FOL-005 peptide for 48 hours (A) (n=7-10 / group). Wound closure rates in HUVECs treated with indicated doses of FOL-005 were quantified by image J software (B) (n=12-14 / group), and representative images at 0 and 6 hours after scratching are shown in (C).

[0097] Fig.30 The effect of FOL-005 peptide on smooth muscle cell proliferation was determined by BrdU incorporation in peptide-treated human coronary artery smooth muscle cells (HCASMC) (A).

[0098] Scratch wound assay of HCASMC incubated with FOL-005 peptide for 5 hours was measured by image J software (B) (n=10-12 / group), and representative pictures of smooth muscle cells migrating into the in vitro scratch are shown in (C). Scale bar=150 um.

[0099] Fig.31 Effect of FOL-005 peptide on tube formation and the role of NRP-1 therein. Representative images of tube formation in human umbilical vascular endothelial cells (HUVEC) treated with FOL-005 peptide are shown in (A and B). Scale bar = 150 um. DETAILED DESCRIPTION

[0100] definition

[0101] As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0102] The term "some embodiments" may include one or more than one embodiments.

[0103] The use of the word "a" or "an" throughout the text or when used in conjunction with the term "comprising" in the claims and / or specification may mean "one / kind", but it is also consistent with the meaning of "one or more / one or more", "at least one / kind", and "one / kind or more than one / kind".

[0104] As used herein, "Preventing" or "Prevention" includes delaying, stopping, reducing the risk of onset of a disease, disorder or condition.

[0105] Pharmacy

[0106] The agent of the present invention may be a peptide; a polynucleotide encoding the peptide; a vector comprising the polynucleotide; or a cell comprising the polynucleotide or the vector.

[0107] Peptides

[0108] In one embodiment, the agent is a peptide or a pharmaceutically acceptable salt thereof.

[0109] As used herein, the term 'amino acid' includes the standard twenty genetically encoded amino acids and their corresponding 'D' stereoisomers (compared to the natural 'L' form), omega-amino acids and other naturally occurring amino acids, unconventional amino acids (e.g., α,α-disubstituted amino acids, N-alkyl amino acids, etc.) and chemically derived amino acids (see below).

[0110] When an amino acid is specifically listed, such as 'alanine' or 'Ala' or 'A', the term refers to both L-alanine and D-alanine unless otherwise expressly stated. Other unconventional amino acids may also be suitable components for the peptides of the present disclosure, as long as the desired functional properties are retained by the peptides. For the peptides shown, each encoded amino acid residue is represented by a single letter name, corresponding to the common name of the conventional amino acid, where appropriate.

[0111] In one embodiment, the peptide is non-naturally occurring, eg, a peptide comprising non-proteinogenic amino acid residues.

[0112] In one embodiment, the agent comprises or consists of a tandem repeat comprising two or more repeating units. In one embodiment, the repeating unit comprises or consists of an amino acid sequence of any one or more sequences as described herein.

[0113] In one embodiment, the peptide is cyclic. The cyclic structure can be realized by any suitable synthetic method. Therefore, heterogeneous linkage can include but is not limited to the formation via disulfide, cysteine, alkylene or sulfide bridges. In one embodiment, the peptide can form at least one intramolecular cysteine ​​bridge.

[0114] In one embodiment, the agent comprises or consists of a peptide comprising or consisting of an amino acid sequence of the following general formula:

[0115] X5X6SX7X8YGLR (SEQ ID NO: 1)

[0116] in:

[0117] X5 is D or G;

[0118] X6 is I or G;

[0119] X7 is V or L; and

[0120] X8 is V or A.

[0121] In one embodiment, the peptide comprises or consists of an amino acid sequence of the following formula:

[0122] VDX2X3X4GX5X6SX7X8YGLR(SEQ ID NO:2)

[0123] in:

[0124] X2 is T or V;

[0125] X3 is Y or P;

[0126] X4 is D or N;

[0127] X5 is D or G;

[0128] X6 is I or G;

[0129] X7 is V or L; and

[0130] X8 is V or A.

[0131] In one embodiment, the peptide comprises or consists of an amino acid sequence of the following formula:

[0132] VDTYX4GX5X6SX7X8YGLR(SEQ ID NO:3)

[0133] in:

[0134] X4 is D or N;

[0135] X5 is D or G;

[0136] X6 is I or G;

[0137] X7 is V or L; and

[0138] X8 is V or A.

[0139] In one embodiment, the peptide comprises or consists of an amino acid sequence of the following formula:

[0140] VDTYDGZ7Z8SZ 10 Z 11 YGLR (SEQ ID NO:4)

[0141] in:

[0142] X5 is D or G;

[0143] X6 is I or G;

[0144] X7 is V or L; and

[0145] X8 is V or A.

[0146] In one embodiment, the peptide comprises or consists of an amino acid sequence of the following formula:

[0147] VDTYDGZ7Z8SVVYGLR(SEQ ID NO:5)

[0148] in:

[0149] X5 is D or G; and

[0150] X6 is I or G;

[0151] In one embodiment, the agent comprises or consists of a peptide comprising or consisting of an amino acid sequence of the following general formula:

[0152] X 14 LX 15 YGIK (SEQ ID NO: 105)

[0153] in:

[0154] X 14 is E or G; and

[0155] X 15 It is S or T.

[0156] In one embodiment, the peptide comprises or consists of an amino acid sequence of the following formula:

[0157] KX9LAX 10 X 11 X 12 X 13 IX 14 LX 15 YGIK (SEQ ID NO: 106)

[0158] in:

[0159] X9 is C, P or G;

[0160] X 10 is E or G;

[0161] X 11 is C, D or I;

[0162] X 12 is D, I, S or G;

[0163] X 13 is S, D or G;

[0164] X 14 is E or G; and

[0165] X 15 It is S or T.

[0166] In one embodiment, the peptide comprises or consists of an amino acid sequence of the following formula:

[0167] KX9LAX 10 X 11 X 12 X 13 IX 14 LSYGIK (SEQ ID NO: 107)

[0168] in:

[0169] X9 is C, P or G;

[0170] X 10 is E or G;

[0171] X 11 is C, I, or absent;

[0172] X 12 is D, G or not present;

[0173] X 13 is S, G, or absent; and

[0174] X 14 It is E or G.

[0175] In one embodiment, the peptide comprises or consists of an amino acid sequence of the following general formula:

[0176] KX9LAX 10 IX 14 LSYGIK (SEQ ID NO: 108)

[0177] in:

[0178] X9 is C, P or G;

[0179] X 10 is E or G; and

[0180] X 14 It is E or G.

[0181] In one embodiment, the peptide comprises or consists of the amino acid sequence IELSYGIK (SEQ ID NO: 109).

[0182] In one embodiment, the peptide comprises VDTYDGGISVVYGLR (SEQ ID NO: 6) or consists of it. In one embodiment, the peptide comprises AEIDSIELSYGIK (SEQ ID NO: 110) or consists of it. In one embodiment, the peptide comprises VDTYDGDISVVYGLR (SEQ ID NO: 7) or consists of it. In one embodiment, the peptide comprises DTYDGDISVVYGLR (SEQ ID NO: 8) or consists of it. In one embodiment, the peptide comprises TYDGDISVVYGLRS (SEQ ID NO: 9) or consists of it. In one embodiment, the peptide comprises TYDGDISVVYGLR (SEQ ID NO: 10) or consists of it. In one embodiment, the peptide comprises YDGDISVVYGLRS (SEQ ID NO: 11) or consists of it. In one embodiment, the peptide comprises YDGDISVVYGLR (SEQ ID NO: 12) or consists of it. In one embodiment, the peptide comprises DGDISVVYGLRS (SEQ ID NO: 13) or consists of it. In one embodiment, the peptide comprises DGDISVVYGLR (SEQ ID NO: 14) or consists of it. In one embodiment, the peptide comprises GDISVVYGLRS (SEQ ID NO: 15) or consists of it. In one embodiment, the peptide comprises GDISVVYGLR (SEQ ID NO: 16) or consists of it. In one embodiment, the peptide comprises DISVVYGLRS (SEQ ID NO: 17) or consists of it. In one embodiment, the peptide comprises DISVVYGLR (SEQ ID NO: 18) or consists of it. In one embodiment, the peptide comprises VDVPNGDISLAYGLR (SEQ ID NO: 19) or consists of it. In one embodiment, the peptide comprises DVPNGDISLAYGLRS (SEQ ID NO: 20) or consists of it. In one embodiment, the peptide comprises DVPNGDISLAYGLR (SEQ ID NO: 21) or consists of it. In one embodiment, the peptide comprises VPNGDISLAYGLRS (SEQ ID NO: 22) or consists of it. In one embodiment, the peptide comprises VPNGDISLAYGLR (SEQ ID NO: 23) or consists thereof. In one embodiment, the peptide comprises PNGDISLAYGLRS (SEQ ID NO: 24) or consists thereof. In one embodiment, the peptide comprises PNGDISLAYGLR (SEQ ID NO: 25) or consists thereof. In one embodiment, the peptide comprises NGDISLAYGLRS (SEQ ID NO: 26) or consists thereof.In one embodiment, the peptide comprises NGDISLAYGLR (SEQ ID NO: 27) or consists of it. In one embodiment, the peptide comprises GDISLAYGLRS (SEQ ID NO: 28) or consists of it. In one embodiment, the peptide comprises GDISLAYGLR (SEQ ID NO: 29) or consists of it. In one embodiment, the peptide comprises DISLAYGLRS (SEQ ID NO: 30) or consists of it. In one embodiment, the peptide comprises DISLAYGLR (SEQ ID NO: 31) or consists of it. In one embodiment, the peptide comprises VDTYDGDGSVVYGLR (SEQ ID NO: 32) or consists of it. In one embodiment, the peptide comprises VDVPEGDISLAYGLR (SEQ ID NO: 33) or consists of it. In one embodiment, the peptide comprises KPLAEIDSIELSYGIK (SEQ ID NO: 111) or consists of it. In one embodiment, the peptide comprises KCLAECDSIELSYGIK (cyclic) (SEQ ID NO: 112) or consists of it. In one embodiment, the peptide comprises KPLAEDISIELSYGIK (SEQ ID NO: 113) or consists of it. In one embodiment, the peptide comprises KPLAEISDIELSYGIK (SEQ ID NO: 114) or consists of it. In one embodiment, the peptide comprises KPLAEIGDIELSYGIK (SEQ ID NO: 115) or consists of it. In one embodiment, the peptide comprises KPLAEGDIELSYGIK (SEQ ID NO: 116) or consists of it. In one embodiment, the peptide comprises KPLAEIELSYGIK (SEQ ID NO: 117) or consists of it. In one embodiment, the peptide comprises KPLAEIDSIELTYGIK (SEQ ID NO: 118) or consists of it. In one embodiment, the peptide comprises KPLAEIDGIELSYGIK (SEQ ID NO: 119) or consists of it. In one embodiment, the peptide comprises KPLAEIDGIELTYGIK (SEQ ID NO: 120) or consists of it. In one embodiment, the peptide comprises or consists of KPLAEIGSIELSYGIK (SEQ ID NO: 121). In one embodiment, the peptide comprises or consists of KGLAEIDSIELSYGIK (SEQ ID NO: 122). In one embodiment, the peptide comprises or consists of KPLAGIDSIGLSYGIK (SEQ ID NO: 123). In one embodiment, the peptide comprises or consists of cyclic KCLAEIDSCELSYGIK (SEQ ID NO: 124).In one embodiment, the peptide comprises LAEIDSIELSYGIK (SEQ ID NO: 125) or consists of it. In one embodiment, the peptide comprises EIDSIELSYGIK (SEQ ID NO: 126) or consists of it. In one embodiment, the peptide comprises IDSIELSYGIK (SEQ ID NO: 127) or consists of it. In one embodiment, the peptide comprises DSIELSYGIK (SEQ ID NO: 128) or consists of it. In one embodiment, the peptide comprises SIELSYGIK (SEQ ID NO: 129) or consists of it. In one embodiment, the peptide comprises IELSYGIK (SEQ ID NO: 109) or consists of it. In one embodiment, the peptide comprises VDTYDGDISVVYGL (SEQID NO: 34) or consists of it. In one embodiment, the peptide comprises VDTYDGDISVVYG (SEQ ID NO: 35) or consists of it. In one embodiment, the peptide comprises VDTYDGDISVVY (SEQ ID NO: 36) or consists of it. In one embodiment, the peptide comprises or consists of VDTYDGDISVV (SEQ ID NO: 37). In one embodiment, the peptide comprises or consists of VDTYDGDISV (SEQ ID NO: 38). In one embodiment, the peptide comprises or consists of VDTYDGDIS (SEQ ID NO: 39). In one embodiment, the peptide comprises or consists of VDTYDGRGDSVVYGLR (SEQ ID NO: 40). In one embodiment, the peptide comprises or consists of VDVPNGDISLAYGL (SEQ ID NO: 41). In one embodiment, the peptide comprises or consists of VDVPNGDISLAYG (SEQ ID NO: 42). In one embodiment, the peptide comprises or consists of VDVPNGDISLA (SEQ ID NO: 43). In one embodiment, the peptide comprises or consists of VDVPNGDIS (SEQ ID NO: 44). In one embodiment, the peptide comprises or consists of GDPNDGRGDSVVYGLR (SEQ ID NO: 45. In one embodiment, the peptide comprises or consists of LDGLVRAYDNISPVG (SEQ ID NO: 46). In one embodiment, the peptide comprises or consists of GDPNGDISVVYGLR (SEQ ID NO: 47). In one embodiment, the peptide comprises or consists of VDVPNGDISLAYRLR (SEQ ID NO: 48). In one embodiment, the peptide comprises or consists of VDVPEGDISLAYRLR (SEQ ID NO: 49).In one embodiment, the peptide comprises or consists of V(beta-D)TYDGDISVVYGLR (SEQ ID NO: 50). In one embodiment, the peptide comprises VDTY(beta-D)GDISVVYGLR (SEQ ID NO: 51 or consists thereof. In one embodiment, the peptide comprises VDTYDG(beta-D)ISVVYGLR (SEQ ID NO: 52) or consists thereof. In one embodiment, the peptide comprises CLAEIDSC(cyclic) (SEQ ID NO: 130) or consists thereof. In one embodiment, the peptide comprises CFKPLAEIDSIECSYGIK(cyclic) (SEQ ID NO: 131) or consists thereof. In one embodiment, the peptide comprises cyclic CFKPLAEIDSIEC (SEQ ID NO: 132) or consists thereof. In one embodiment, the peptide comprises KPLAEIDSIELSYGI (SEQ ID NO: 133) or consists thereof. In one embodiment, the peptide comprises KPLAEIDSIELSYG (SEQ ID NO: 134) or consists thereof. In one embodiment, the peptide comprises KPLAEIDSIELSY (SEQ ID NO: 135), KPLAEIDSIELS (SEQ ID NO: 136). In one embodiment, the peptide comprises or consists of KPLAEIDSIEL (SEQ ID NO: 137). In one embodiment, the peptide comprises or consists of KPLAEIDSIE (SEQ ID NO: 138).

[0183] Salts and Prodrugs

[0184] The medicament as defined herein may be in the form of a pharmaceutically acceptable salt or prodrug of the medicament. In one embodiment, the medicament as defined herein may be formulated as a pharmaceutically acceptable addition salt or hydrate of the medicament such as, but not limited to, K + 、Na + , and non-salts such as H + .

[0185] Modification

[0186] In one embodiment, the agent is a chemical derivative of a peptide. Chemical derivatives of one or more amino acids can be obtained by reaction with functional side groups. Such derivatives include, for example, molecules in which free amino groups have been derivatized to form amine hydrochlorides, p-toluenesulfonyl groups, carboxyphenoxy groups, tert-butyloxycarbonyl groups, chloroacetyl groups, or formyl groups. Free carboxyl groups can be derivatized to form salts, methyl and ethyl esters or other types of esters and hydrazides. Free hydroxyl groups can be derivatized to form O-acyl or O-alkyl derivatives. Also included as chemical derivatives are those peptides that contain naturally occurring amino acid derivatives of the twenty standard amino acids. For example: 4-hydroxyproline can replace proline; 5-hydroxylysine can replace lysine; 3-methylhistidine can replace histidine; homoserine can replace serine, and ornithine can replace lysine. Derivatives also include peptides containing one or more additions or deletions, as long as the necessary activity is maintained. Other modifications included are amidation, amino terminal acylation (eg, acetylation or thioglycolic acid amidation), terminal carboxyl amidation (eg, with ammonia or methylamine), and similar terminal modifications.

[0187] In one embodiment, the agent is further modified, for example, by glycosylation, pegylation, amidation, esterification, acylation, acetylation, and / or alkylation.

[0188] In some embodiments, the agent is further conjugated to a moiety that can be selected from the group consisting of polyethylene glycol (PEG), a monosaccharide, a fluorophore, a chromophore, a radioactive compound, and a cell penetrating peptide. In one embodiment, the fluorophore is selected from the group consisting of fluorescein, biotin, 5,6-carboxytetramethylrhodamine (TAMRA), indodicarbocyanine (C5), Alexa Fluor®, 488. Alexa 532. Alexa 647, ATTO 488, ATTO 532, 6-carboxyfluorescein (6-FAM), Alexa 350, DY-415, ATTO 425, ATTO 465, FL, fluorescein isothiocyanate, Oregon 488. Oregon 514、Rhodamine Green TM (Rhodamine Green TM ), 5'-tetrachlorofluorescein, ATTO 520, 6-carboxy-4',5'-dichloro-2',7'-dimethoxyfluorescein, Yakima Yellow TM dye, 530 / 550, hexachlorofluorescein, Alexa 555, DY-549, TMR-X, cyanine phosphoramidites (cyanine 3, cyanine 3.5, cyanine 5, cyanine 5.5, cyanine 7.5), ATTO 550, Rhodamine Red TM (Rhodamine Red TM ), ATTO 565, carboxy-X-rhodamine, Texas Red (sulforhodamine 101 sulfonyl chloride), Red 610, ATTO 594, DY-480-XL, DY-610, ATTO 610, Red 640, Bodipy 630 / 650, ATTO633, Bodipy 650 / 665, ATTO 647N, DY-649, Red 670, ATTO 680, Red 705, DY-682, ATTO 700, ATTO 740, DY-782, IRD 700, IRD 800, CAL Gold 540nm, CAL Gold 522nm, CAL Gold 544nm, CAL Orange 560nm, CAL Orange 538nm, CAL Orange 559nm, CAL Red 590nm, CAL Red 569nm, CAL Red 591nm, CAL Red 610nm, CAL Red 590nm, CAL Red 610nm, CAL Red 635nm, 570nm, 548nm, 566nm(Cy 3), 670nm, 647nm, 670nm, 705nm, 690nm, 705nm(Cy 5.5), 650 dyes, In one embodiment, the agent further comprises a detectable moiety, e.g., a moiety detectable by imaging techniques such as SPECT, PET, MRI, optical or ultrasound imaging. In one embodiment, the detectable moiety comprises, e.g., a moiety selected from 99mTc, 111 In, 67 Ga, 68 Ga, 72 As, 89 Zr, 123 I and 201 or consisting of a radioactive isotope of the group consisting of Tl.

[0189] In one embodiment, the peptide comprises or consists of a fusion. For example, the peptide may comprise a fusion of two amino acid sequences as disclosed herein.

[0190] The term 'fusion' of a peptide relates to an amino acid sequence fused to another peptide. For example, the peptide can be fused to a polypeptide such as glutathione-S-transferase (GST) or protein A to facilitate purification of the peptide. Examples of such fusions are well known to those skilled in the art. Similarly, the peptide can be fused to an oligohistidine tag such as His6, or to an epitope recognized by an antibody such as the well-known Myc tag epitope. Fusions with any variant or derivative of the peptide are also included within the scope of the present disclosure. Alternatively, the fusion moiety can be a lipophilic molecule or peptide domain capable of promoting cellular uptake of the polypeptide, as known to those skilled in the art.

[0191] Peptide length

[0192] In one embodiment, the length of the peptide is no more than 85 amino acids, for example no more than 80 amino acids, for example no more than 75 amino acids, for example no more than 70 amino acids, for example no more than 65 amino acids, for example no more than 60 amino acids, for example no more than 55 amino acids, for example no more than 50 amino acids, for example no more than 55 amino acids, for example no more than 40 amino acids, for example no more than 35 amino acids, for example no more than 30 amino acids, for example no more than 28 amino acids, for example no more than 26 amino acids, for example no more than 24 amino acids, for example no more than 22 amino acids, for example no more than 20 amino acids, for example no more than 19 amino acids, for example no more than 18 amino acids, for example no more than 17 amino acids, for example no more than 16 amino acids, for example no more than 15 amino acids, for example no more than 14 amino acids, for example no more than 13 amino acids, for example no more than 12 amino acids, for example no more than 11 amino acids, for example no more than 10 amino acids.

[0193] In one embodiment, the peptide comprises at least 2 additional amino acids, such as at least 3 amino acids, such as at least 4 amino acids, such as at least 5 amino acids, such as at least 6 amino acids, such as at least 7 amino acids, such as at least 8 amino acids, such as at least 9 amino acids, such as at least 10 amino acids, such as at least 15 amino acids or such as at least 20 amino acids conjugated to the N- or C-terminus of the peptide.

[0194] In one embodiment the peptide is 5 to 30 amino acids in length, such as 5 to 20 amino acids, such as 8 to 20 amino acids, such as 8 to 18 amino acids, for example 10 to 16 amino acids in length.

[0195] In one embodiment, when X 14 When is T, the peptide contains no more than 25 amino acid residues.

[0196] In another embodiment, the agent is a fragment of a peptide described herein, and the fragment comprises 15 or fewer amino acids in length, such as less than 14 amino acids, such as less than 13 amino acids, such as less than 12 amino acids, such as less than 11 amino acids, such as less than 10 amino acids, such as less than 9 amino acids, such as less than 8 amino acids, such as less than 7 amino acids, such as less than 6 amino acids, such as less than 5 amino acids in length.

[0197] By "fragment", at least 5 consecutive amino acids of an amino acid sequence are included, such as at least 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 consecutive amino acids of an amino acid sequence. A fragment may be 15 or fewer amino acids in length, such as 14, 13, 12, 11, 10, 9, 8, 7, 6 or 5 amino acids in length.

[0198] Variants

[0199] In one embodiment, the agent is a variant of a peptide as described herein, wherein the variant comprises or consists of a sequence in which any one amino acid has been changed to another proteinogenic or non-proteinogenic amino acid, provided that no more than five amino acids are so changed.

[0200] The term "variant" refers to a peptide that does not have 100% amino acid sequence identity with a parent peptide, i.e., one or more amino acids must be mutated. "Mutated" refers to an amino acid that is changed at a specified position in a parent peptide. For example, the amino acid at a specified position can be deleted, changed, substituted, or can be an insertion / addition site for one or more amino acids. It will be appreciated by those skilled in the art that substitutions can be conservative or non-conservative.

[0201] In one embodiment, the peptide variant comprises or consists of a sequence in which no more than five amino acids are changed to another proteinogenic or non-proteinogenic amino acid, such as no more than 4 amino acids, such as no more than 3 amino acids, such as no more than 2 amino acids, such as no more than 1 amino acid is changed. In one embodiment, one or more amino acids are conservatively substituted. "Conservatively substituted" refers to the substitution of an amino acid by another amino acid with similar properties (size, hydrophobicity, etc.) so that the function of the peptide is not significantly changed. Therefore, "conservative substitution" means a combination such as Gly, Ala; Val, Ile, Leu; Asp, Glu; Asn, Gln; Ser, Thr; Lys, Arg; and Phe, Tyr.

[0202] In one embodiment, the peptide has an additional amino acid. In one embodiment, the peptide comprises or consists of one or more additional amino acids inserted at the N- and / or C-terminal end and / or within the sequence. In one embodiment, at least 2 additional amino acids are inserted, such as at least 3, such as at least 4, such as at least 5, such as at least 6, such as at least 7, such as at least 8, such as at least 9, such as at least 10, such as at least 15 or such as at least 20 additional amino acids.

[0203] In one embodiment, the agent increases angiogenesis in a subject. In one embodiment, the agent is an angiogenesis inducer. In one embodiment, the agent is capable of improving myocyte survival in cardiovascular disease. In one embodiment, the agent is capable of improving neuronal survival in cerebrovascular disease.

[0204] Polynucleotides, vectors and cells

[0205] In one embodiment, the agent is a polynucleotide that encodes a peptide as described herein when expressed. In one embodiment, the agent is a vector comprising a polynucleotide as described herein. In an embodiment, the agent is a cell comprising a polynucleotide or vector as described herein.

[0206] Composition and coating

[0207] In one embodiment, the medicament is a composition. In one embodiment, the composition is a pharmaceutical composition. In one embodiment, the composition is a cosmetic composition. In one embodiment, the composition is a coating.

[0208] Coatings on various implants are known in the art. Applications in humans include central venous catheters, coronary stents, ventricular assist devices, extracorporeal blood circuits, blood sampling devices, and artificial blood vessels. Such coatings can be in gel or non-gel form. As used herein, "coatings comprising agents" include agents adsorbed to surfaces, bound to surfaces, and embedded in polymer surfaces.

[0209] Implants

[0210] In one aspect, the invention relates to an implant comprising an agent as described herein. In one embodiment, the implant is coated with a composition comprising the agent. Thus, the agent can, for example, be adsorbed to the surface, bound to the surface, and embedded in the polymer surface of the implant.

[0211] In one embodiment, the implant is an implant of a biological material, such as bone.

[0212] In one embodiment, the implant is a medical device, such as a stent.

[0213] Medical Uses

[0214] The agents disclosed herein have been shown to induce angiogenesis. This property can be used to treat a variety of diseases and conditions. Such diseases and conditions will generally be associated with abnormal levels of angiogenesis, such as reduced angiogenesis compared to healthy tissue.

[0215] One embodiment of the present disclosure provides an agent as disclosed herein for use in increasing angiogenesis in a subject.

[0216] One embodiment of the present disclosure provides an agent as disclosed herein for use as an angiogenesis inducing agent.

[0217] It may be desirable to increase angiogenesis in the myocardium, for example by increasing angiogenesis in the affected tissue. Various cardiovascular diseases are associated with ischemia, for example, reduced oxygen supply to the affected tissue. Thus, one embodiment of the present disclosure provides an agent as disclosed herein for use in improving myocyte survival in cardiovascular disease.

[0218] Certain cerebrovascular diseases are associated with reduced oxygen flow to the affected tissue. Increasing vascularization of the affected tissue, for example to improve oxygen supply, may be beneficial. One embodiment of the present disclosure provides an agent as disclosed herein for use in improving neuronal cell survival in cerebrovascular diseases.

[0219] One embodiment of the present disclosure provides an agent as disclosed herein for use in treating a disease or disorder associated with reduced or impaired angiogenesis.

[0220] One embodiment of the present disclosure provides a method for inducing angiogenesis, the method comprising administering an agent of the present disclosure to a subject.

[0221] Many diseases and conditions are associated with reduced or impaired vascularization, or can be beneficially ameliorated by increasing vascularization in affected tissues. One embodiment of the present disclosure provides an agent as disclosed herein for use in treating or preventing a disease or condition in a subject, wherein the disease or condition is selected from the group consisting of:

[0222] i. Diseases of the circulatory system,

[0223] ii. Damage caused by external factors,

[0224] iii. Diseases of the immune system,

[0225] iv. Diseases of the nervous system, and

[0226] v. Diseases of the musculoskeletal system or connective tissue.

[0227] Diseases of the circulatory system refer to diseases of organ systems that deliver nutrients (e.g., amino acids, electrolytes, and lymph), gases, hormones, blood cells, etc. to or from cells in the body to help resist disease, stabilize body temperature and pH, and maintain homeostasis. Damage from external causes means physical or physiological bodily injuries caused by the interaction of the body with energy (mechanical, thermal, electrical, chemical, or radiation, or due to extreme pressure), the amount of energy or the rate of transfer exceeding the body or physiological tolerance. Damage may also be caused by the lack of important elements such as oxygen. Including poisoning by substances and the toxic effects of substances, such as the damage of implanted devices or due to implanted devices. Damage is usually rapid in response to well-defined events (e.g., car accidents, hitting the ground after falling, drinking highly alkaline liquids, drug overdose, burns sustained during surgical procedures). These events are often referred to as external causes of damage. However, the energy of injury can be derived from the injured individual and / or his or her immediate environment (e.g., individuals running in hot weather suffer heat exhaustion), and damage can be caused by the injured individual (i.e., intentional self-mutilation). Impairments include manifestations that are evident immediately after onset, which may or may not persist, and manifestations that first become evident at a later time.

[0228] In one embodiment, the disease or condition associated with reduced or impaired angiogenesis is a complication associated with a disease or condition selected from the group consisting of:

[0229] i. Diseases of the circulatory system,

[0230] ii. Damage caused by external factors,

[0231] iii. Diseases of the immune system,

[0232] iv. Circulatory system symptoms, signs or clinical findings,

[0233] v. Diseases of the myocardium or heart chambers, and

[0234] vi. Endocrine, nutritional or metabolic diseases.

[0235] One embodiment of the present disclosure provides a medicament as disclosed herein for use in treating or preventing complications associated with a disease or disorder selected from the group consisting of:

[0236] vii. Diseases of the circulatory system,

[0237] viii. Damage caused by external factors,

[0238] ix. Diseases of the immune system,

[0239] x. Circulatory system symptoms, signs or clinical findings,

[0240] xi. Diseases of the myocardium or heart chambers, and

[0241] xii. Endocrine, nutritional or metabolic diseases.

[0242] In one embodiment of the present disclosure, the disease of the circulatory system is selected from the group consisting of:

[0243] i.Ischemic heart disease,

[0244] ii. Cerebrovascular disease,

[0245] iii. Coronary artery disease,

[0246] iv. Diseases of arteries, arterioles or capillaries,

[0247] v. Circulatory system symptoms, signs or clinical findings,

[0248] vi. Diseases of the myocardium or heart chambers, and

[0249] vii. Endocrine, nutritional or metabolic diseases.

[0250] Cerebrovascular disease is a group of brain disorders associated with disease of the blood vessels supplying the brain. This includes "stroke", which includes the following entities - intracerebral hemorrhage; subarachnoid hemorrhage; ischemic stroke, and stroke not known to be ischemic or hemorrhagic.

[0251] Clinical findings of the circulatory system include those found using physical, laboratory, and imaging techniques. Disease can manifest in a variety of ways and in different body systems. Such specific manifestations may be a reason for treatment or a visit, with or without identification or resolution of the underlying condition. This includes less clearly defined conditions and symptoms, which may be designated as 'not otherwise specified', 'unexplained', or 'transient' where it is necessary to study the case to determine the final diagnosis. The included conditions and signs or symptoms consist of the following: cases where a more definitive diagnosis cannot be made even if all facts related to the case have been investigated; signs or symptoms present at the time of the initial visit, which prove to be transient and whose cause cannot be determined; temporary diagnoses in patients who have failed to return for further investigation or care; cases where the patient has been referred elsewhere for investigation or treatment before a diagnosis is made; cases where a more precise diagnosis cannot be obtained for any other reason; and certain symptoms for which additional information is provided, which themselves represent important issues in health care.

[0252] Diseases of the myocardium or heart chambers include diseases of the involuntary striated muscles found in the heart wall and histologically (specifically the atria and ventricles), as well as diseases of the myocardium itself.

[0253] In one embodiment of the present disclosure, the ischemic heart disease is selected from the group consisting of:

[0254] i. acute ischemic heart disease, such as myocardial infarction, such as acute myocardial infarction and unspecified acute ischemic heart disease (acute coronary syndrome),

[0255] ii. Chronic ischemic heart disease, such as other specific chronic ischemic heart disease (cardiovascular arteriosclerosis),

[0256] iii. Angina pectoris, such as unstable angina, and

[0257] iv. Obstructive arteriosclerosis.

[0258] Chronic heart disease is seen due to atherosclerosis of the coronary arteries. It is characterized by angina pectoris and unstable angina pectoris.

[0259] In one embodiment, the myocardial infarction is ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI). In one embodiment, the presence of STEMI or NSTEMI is accompanied by certain current complications later, for example within a period of 28 days.

[0260] In one embodiment, the disease of the circulatory system is cardiovascular sclerosis.In one embodiment, the disease of the circulatory system is or is associated with systemic sclerosis.

[0261] In one embodiment, the cerebrovascular disease is selected from the group consisting of:

[0262] i. Cerebral ischemia, such as ischemic stroke (stroke), such as cerebral infarction, and

[0263] ii. Asymptomatic stenosis of intracranial or extracranial arteries (cerebral arteriosclerosis).

[0264] Acute focal neurologic dysfunction caused by focal infarction at one or more sites in the brain. Evidence of acute infarction may come from a) symptoms lasting longer than 24 hours, or b) neuroimaging or other techniques in clinically relevant areas of the brain.

[0265] In one embodiment, ischemic stroke is associated with a patient history of transient ischemic attack (TIA) or cerebral infarction without residual defects. The transient onset of focal neurological dysfunction is caused by focal cerebral ischemia without acute infarction in the clinically relevant area of ​​the brain, or by transient monocular vision loss due to retinal ischemia. Symptoms should completely subside within 24 hours.

[0266] In one embodiment, the ischemic stroke is associated with a patient history of traumatic brain injury or sequelae of cerebrovascular disease.

[0267] In one embodiment, the cerebrovascular disease is selected from the group consisting of:

[0268] i. Non-traumatic subarachnoid hemorrhage,

[0269] ii. Non-traumatic intracerebral hemorrhage,

[0270] iii. Other and unspecified non-traumatic intracranial hemorrhage,

[0271] iv. Cerebral infarction,

[0272] v. Occlusion and stenosis of the precerebral arteries that do not lead to cerebral infarction,

[0273] vi. Occlusion and stenosis of cerebral arteries that do not lead to cerebral infarction,

[0274] vii. Other cerebrovascular diseases,

[0275] viii. Cerebrovascular disorders associated with other diseases (cerebrovascular disorders classified in other sites), and

[0276] ix. Sequelae of cerebrovascular disease.

[0277] In one embodiment, the disease of an artery, arteriole or capillary is selected from the group consisting of:

[0278] i. Atherosclerosis,

[0279] ii. Aortic aneurysm and dissection,

[0280] iii. Other aneurysms,

[0281] iv. Other peripheral vascular diseases,

[0282] v. Arterial embolism and thrombosis,

[0283] vi. Atherosclerotic embolism,

[0284] vii. Septic arterial embolism,

[0285] viii. Other diseases of arteries and arterioles,

[0286] ix. Diseases of the capillaries, and

[0287] x. A disorder of the arteries, arterioles, or capillaries associated with another disease (a disorder of the arteries, arterioles, or capillaries classified under Diseases of Other Sites).

[0288] In one embodiment, the disease of the arteries, arterioles or capillaries is chronic arterial occlusive disease, such as atherosclerotic chronic arterial occlusive disease or vascular sclerosis.

[0289] In one embodiment, the circulatory symptom, sign, or clinical finding is a symptom or sign involving the circulatory system, such as an undiagnosed abnormal blood pressure reading, such as cardiac arrest.

[0290] In one embodiment, the disease of the myocardium or a heart chamber is a cardiomyopathy, such as dilated cardiomyopathy. These are myocardial disorders in which the myocardium is structurally and functionally abnormal in the absence of coronary artery disease, hypertension, valvular disease, and congenital heart disease sufficient to cause the observed myocardial abnormalities.

[0291] In one embodiment, the disease of the immune system is a non-organ specific systemic autoimmune disorder, such as a vasculitis, eg, thromboangiitis obliterans (Buerger's disease).

[0292] In one embodiment, the disease of the nervous system is selected from the group consisting of:

[0293] i. Movement disorders, such as Parkinson's syndrome, such as Parkinson's disease,

[0294] ii. Multiple sclerosis or other white matter disorders, such as multiple sclerosis, and

[0295] iii. Conditions with neurocognitive impairment as a predominant feature, such as Alzheimer's disease.

[0296] In one embodiment, the disease of the musculoskeletal system or connective tissue is a condition related to the spine, such as a herniated disc.

[0297] In one embodiment, the disease of the circulatory system, the immune system, the nervous system, or the musculoskeletal system or connective tissue is or is associated with diabetes. In one embodiment, diabetes is selected from type 1 diabetes and type 2 diabetes. In one embodiment, the subject suffers from diabetes.

[0298] In one embodiment, the subject is a mammal. In one embodiment, the mammal is a human.

[0299] One embodiment of the present disclosure provides a method for treating or preventing a disease or condition in a subject, wherein the disease or condition is selected from the group consisting of:

[0300] i. Diseases of the circulatory system,

[0301] ii. Damage caused by external factors,

[0302] iii. Diseases of the immune system,

[0303] iv. Diseases of the nervous system, and

[0304] v. Diseases of the musculoskeletal system or connective tissue,

[0305] The method comprises administering to a subject in need thereof a therapeutically effective amount of an agent as defined herein.

[0306] One embodiment of the present disclosure provides the use of an agent as defined herein for the manufacture of a medicament for the treatment or prevention of a disease or condition selected from the group consisting of:

[0307] i. Diseases of the circulatory system,

[0308] ii. Damage caused by external factors,

[0309] iii. Diseases of the immune system,

[0310] iv. Diseases of the nervous system, and

[0311] v. Diseases of the musculoskeletal system or connective tissue.

[0312] One aspect of the present disclosure provides an agent as disclosed herein for use in increasing angiogenesis in a subject.

[0313] One aspect of the present disclosure provides an agent as disclosed herein for use as an angiogenesis inducing agent.

[0314] One aspect of the present disclosure provides an agent as disclosed herein for use in treating a disease or disorder associated with reduced or impaired angiogenesis.

[0315] One aspect of the present disclosure provides a method for inducing angiogenesis, the method comprising administering an agent of the present disclosure to a subject.

[0316] One aspect of the present disclosure provides an agent as disclosed herein for use in treating or preventing a disease or disorder in a subject, wherein the disease or disorder is selected from the group consisting of:

[0317] i. Diseases of the circulatory system,

[0318] ii. Damage caused by external factors,

[0319] iii. Diseases of the immune system,

[0320] iv. Diseases of the nervous system, and

[0321] v. Diseases of the musculoskeletal system or connective tissue.

[0322] One aspect of the present disclosure provides a medicament as disclosed herein for use in treating or preventing complications associated with a disease or disorder selected from the group consisting of:

[0323] i. Diseases of the circulatory system,

[0324] ii. Damage caused by external factors,

[0325] iii. Diseases of the immune system,

[0326] iv. Circulatory system symptoms, signs or clinical findings,

[0327] v. Diseases of the myocardium or heart chambers, and

[0328] vi. Endocrine, nutritional or metabolic diseases.

[0329] Surgery, Implants and Transplants

[0330] One embodiment of the present disclosure provides an agent of the present disclosure for improving postoperative vascularization. In one embodiment, the surgery is a surgery of the cardiovascular system. In one embodiment, the surgery of the cardiovascular system is a vascular transplant. In one embodiment, the implant is an implant of a biomaterial. In one embodiment, the biomaterial is bone. In one embodiment, the implant is a medical device. In one embodiment, the medical device is a stent.

[0331] One embodiment of the present disclosure provides a disclosed medicament for increasing angiogenesis in a subject undergoing or having undergone a transplant. In one embodiment, the transplant is a transplant of an organ, tissue, or cell. In one embodiment, the transplant of cells is a transplant of bone marrow cells. In one embodiment, the transplant of an organ is a transplant of heart or cardiovascular tissue.

[0332] project

[0333] 1. A medicament comprising:

[0334] a) a peptide selected from the group consisting of:

[0335] (i) a peptide comprising or consisting of an amino acid sequence of the following general formula:

[0336] X5X6SX7X8YGLR (SEQ ID NO: 1)

[0337] in:

[0338] X5 is D or G;

[0339] X6 is I or G;

[0340] X7 is V or L;

[0341] X8 is V or A;

[0342] (ii) a peptide comprising or consisting of an amino acid sequence of the following general formula:

[0343] X 14 LX 15 YGIK (SEQ ID NO: 105)

[0344] in:

[0345] X 14 is E or G;

[0346] X 15 is S or T;

[0347] (iii) a peptide comprising or consisting of an amino acid sequence selected from the group consisting of:

[0348] VDTYDGDISVVYGL(SEQ ID NO:34),

[0349] VDTYDGDISVVYG(SEQ ID NO:35),

[0350] VDTYDGDISVVY (SEQ ID NO: 36),

[0351] VDTYDGDISVV (SEQ ID NO:37),

[0352] VDTYDGDISV (SEQ ID NO:38),

[0353] VDTYDGDIS (SEQ ID NO:39),

[0354] VDTYDGRGDSVVYGLR (SEQ ID NO:40),

[0355] VDVPNGDISLAYGL (SEQ ID NO:41),

[0356] VDVPNGDISLAYG (SEQ ID NO:42),

[0357] VDVPNGDISLA (SEQ ID NO:43),

[0358] VDVPNGDIS (SEQ ID NO:44),

[0359] GDPNDGRGDSVVYGLR (SEQ ID NO:45),

[0360] LDGLVRAYDNISPVG (SEQ ID NO:46),

[0361] GDPNGDISVVYGLR (SEQ ID NO:47)

[0362] VDVPNGDISLAYRLR (SEQ ID NO:48),

[0363] VDVPEGDISLAYRLR (SEQ ID NO:49),

[0364] V(beta-D)TYDGDISVVYGLR (SEQ ID NO:50),

[0365] VDTY(beta-D)GDISVVYGLR (SEQ ID NO:51),

[0366] VDTYDG(beta-D)ISVVYGLR (SEQ ID NO:52);

[0367] CLAEIDSC (circular) (SEQ ID NO:130),

[0368] CFKPLAEIDSIECSYGIK (circular) (SEQ ID NO:131),

[0369] cyclic CFKPLAEIDSIEC (SEQ ID NO: 132),

[0370] KPLAEIDSIELSYGI(SEQ ID NO:133),

[0371] KPLAEIDSIELSYG(SEQ ID NO:134),

[0372] KPLAEIDSIELSY(SEQ ID NO:135),

[0373] KPLAEIDSIELS(SEQ ID NO:136),

[0374] KPLAEIDSIEL (SEQ ID NO: 137), and

[0375] KPLAEIDSIE (SEQ ID NO: 138);

[0376] b) a polynucleotide which, when expressed, encodes the peptide of a);

[0377] c) a vector comprising the polynucleotide of b); or

[0378] d) A cell comprising the polynucleotide of b) or the vector of c).

[0379] 2. The agent according to item 1, wherein the peptide comprises an amino acid sequence of the following general formula:

[0380] VDX2X3X4GX5X6SX7X8YGLR(SEQ ID NO:2)

[0381] in:

[0382] X2 is T or V;

[0383] X3 is Y or P;

[0384] X4 is D or N;

[0385] X5 is D or G;

[0386] X6 is I or G;

[0387] X7 is V or L; and

[0388] X8 is V or A.

[0389] 3. The agent according to any one of the preceding items, wherein the peptide comprises an amino acid sequence of the following general formula:

[0390] VDTYX4GX5X6SX7X8YGLR(SEQ ID NO:3)

[0391] in:

[0392] X4 is D or N;

[0393] X5 is D or G;

[0394] X6 is I or G;

[0395] X7 is V or L; and

[0396] X8 is V or A.

[0397] 4. The agent according to any one of the preceding items, wherein the peptide comprises an amino acid sequence of the following general formula:

[0398] VDTYDGZ7Z8SZ 10 Z 11 YGLR (SEQ ID NO:4)

[0399] in:

[0400] X5 is D or G;

[0401] X6 is I or G;

[0402] X7 is V or L; and

[0403] X8 is V or A.

[0404] 5. The agent according to any one of the preceding items, wherein the peptide comprises an amino acid sequence of the following general formula:

[0405] VDTYDGZ7Z8SVVYGLR(SEQ ID NO:5)

[0406] in:

[0407] X5 is D or G; and

[0408] X6 is I or G;

[0409] 6. The agent according to item 1, wherein the peptide comprises an amino acid sequence of the following general formula:

[0410] KX9LAX 10 X 11 X 12 X 13 IX 14 LX 15 YGIK (SEQ ID NO: 106)

[0411] in:

[0412] X9 is C, P or G;

[0413] X10 is E or G;

[0414] X 11 is C, D or I;

[0415] X 12 is D, I, S or G;

[0416] X 13 is S, D or G;

[0417] X 14 is E or G; and

[0418] X 15 It is S or T.

[0419] 7. The agent according to item 1, wherein the peptide comprises an amino acid sequence of the following general formula:

[0420] KX9LAX 10 X 11 X 12 X 13 IX 14 LSYGIK (SEQ ID NO: 107)

[0421] in:

[0422] X9 is C, P or G;

[0423] X 10 is E or G;

[0424] X 11 is C, I, or absent;

[0425] X 12 is D, G or not present;

[0426] X 13 is S, G, or absent; and

[0427] X 14 It is E or G.

[0428] 8. The agent according to item 1, wherein the peptide comprises an amino acid sequence of the following general formula:

[0429] KX9LAX 10 IX 14 LSYGIK (SEQ ID NO: 108)

[0430] in:

[0431] X9 is C, P or G;

[0432] X 10 is E or G; and

[0433] X 14 It is E or G.

[0434] 9. The agent according to item 1, wherein the peptide comprises the amino acid sequence IELSYGIK (SEQ ID NO: 109).

[0435] 10. The drug according to item 1, provided that if X 14 is T, then the peptide contains no more than 25 amino acid residues.

[0436] 11. The agent according to item 1, wherein the peptide comprises or consists of an amino acid sequence selected from the group consisting of:

[0437] VDTYDGGISVVYGLR(SEQ ID NO:6),

[0438] VDTYDGDISVVYGLR(SEQ ID NO:7),

[0439] DTYDGDISVVYGLR(SEQ ID NO:8),

[0440] TYDGDISVVYGLRS(SEQ ID NO:9),

[0441] TYDGDISVVYGLR(SEQ ID NO:10),

[0442] YDGDISVVYGLRS(SEQ ID NO:11),

[0443] YDGDISVVYGLR (SEQ ID NO: 12),

[0444] DGDISVVYGLRS (SEQ ID NO: 13),

[0445] DGDISVVYGLR (SEQ ID NO: 14),

[0446] GDISVVYGLRS (SEQ ID NO: 15),

[0447] GDISVVYGLR (SEQ ID NO: 16),

[0448] DISVVYGLRS (SEQ ID NO: 17),

[0449] DISVVYGLR (SEQ ID NO: 18),

[0450] VDVPNGDISLAYGLR(SEQ ID NO:19),

[0451] DVPNGDISPLAYGLRS (SEQ ID NO:20),

[0452] DVPNGDISPLAYGLR (SEQ ID NO:21),

[0453] VPNGDISPLAYGLRS (SEQ ID NO:22),

[0454] VPNGDISPLAYGLR (SEQ ID NO:23),

[0455] PNGDISPLAYGLRS (SEQ ID NO:24),

[0456] PNGDISPLAYGLR (SEQ ID NO:25),

[0457] NGDISPLAYGLRS (SEQ ID NO:26),

[0458] NGDISPLAYGLR (SEQ ID NO:27),

[0459] GDISPLAYGLRS (SEQ ID NO:28),

[0460] GDISPLAYGLR (SEQ ID NO:29),

[0461] DISPLAYGLRS (SEQ ID NO:30),

[0462] DISPLAYGLR (SEQ ID NO:31),

[0463] VDTYDGDGSVVYGLR (SEQ ID NO:32),

[0464] VDVPEGDISPLAYGLR (SEQ ID NO:33).

[0465] AEIDSIELSYGIK (SEQ ID NO:110),

[0466] KPLAEIDSIELSYGIK (SEQ ID NO:111),

[0467] KCLAECDSIELSYGIK (circular) (SEQ ID NO:112),

[0468] KPLAEDISIELSYGIK (SEQ ID NO:113),

[0469] KPLAEISDIELSYGIK (SEQ ID NO:114),

[0470] KPLAEIGDIELSYGIK (SEQ ID NO:115),

[0471] KPLAEGDIELSYGIK (SEQ ID NO:116),

[0472] KPLAEIELSYGIK (SEQ ID NO:117),

[0473] KPLAEIDSIELTYGIK (SEQ ID NO:118),

[0474] KPLAEIDGIELSYGIK (SEQ ID NO:119),

[0475] KPLAEIDGIELTYGIK (SEQ ID NO:120),

[0476] KPLAEIGSIELSYGIK (SEQ ID NO:121),

[0477] KGLAEIDSIELSYGIK (SEQ ID NO:122),

[0478] KPLAGIDSIGLSYGIK (SEQ ID NO:123),

[0479] Cyclic KCLAEIDSCELSYGIK (SEQ ID NO:124),

[0480] LAEIDSIELSYGIK (SEQ ID NO:125),

[0481] EIDSIELSYGIK (SEQ ID NO:126),

[0482] IDSIELSYGIK (SEQ ID NO:127),

[0483] DSIELSYGIK (SEQ ID NO:128),

[0484] SIELSYGIK (SEQ ID NO:129), and

[0485] IELSYGIK (SEQ ID NO:109).

[0486] 12. The agent according to item 1, wherein the peptide comprises or consists of the amino acid sequence VDTYDGGISVVYGLR (SEQ ID NO: 6).

[0487] 13. The agent according to item 1, wherein the peptide comprises or consists of the amino acid sequence VDTYDGDISVVYGLR (SEQ ID NO: 7).

[0488] 14. The agent according to item 1, wherein the peptide comprises or consists of the amino acid sequence AEIDSIELSYGIK (SEQ ID NO: 110).

[0489] 15. The agent according to any of the preceding items, wherein the peptide comprises no more than 85 amino acids, for example no more than 80 amino acids, for example no more than 75 amino acids, for example no more than 70 amino acids, for example no more than 65 amino acids, for example no more than 60 amino acids, for example no more than 55 amino acids, for example no more than 50 amino acids, for example no more than 55 amino acids, for example no more than 40 amino acids, for example no more than 35 amino acids, for example no more than 30 amino acids, for example no more than 28 amino acids, for example no more than 26 amino acids, for example no more than 24 amino acids, for example no more than 22 amino acids, for example no more than 20 amino acids, for example no more than 19 amino acids, for example no more than 18 amino acids, for example no more than 17 amino acids, for example no more than 16 amino acids, for example no more than 15 amino acids, for example no more than 14 amino acids, for example no more than 13 amino acids, for example no more than 12 amino acids, for example no more than 11 amino acids, for example no more than 10 amino acids.

[0490] 16. An agent according to any of the preceding items, wherein the peptide comprises at least 2 additional amino acids, such as at least 3 amino acids, such as at least 4 amino acids, such as at least 5 amino acids, such as at least 6 amino acids, such as at least 7 amino acids, such as at least 8 amino acids, such as at least 9 amino acids, such as at least 10 amino acids, such as at least 15 amino acids or such as at least 20 amino acids, conjugated to the N- or C-terminus of the peptide.

[0491] 17. An agent according to any of the preceding items, wherein the agent is non-naturally occurring.

[0492] 18. The agent according to any of the preceding items, wherein the agent is conjugated to a moiety.

[0493] 19. The agent according to item 15, wherein the moiety is selected from the group consisting of polyethylene glycol (PEG), a monosaccharide, a fluorophore, a chromophore, a radioactive compound and a cell penetrating peptide.

[0494] 20. The agent according to any of the preceding items, wherein the agent is further modified, for example by glycosylation, pegylation, amidation, esterification, acylation, acetylation and / or alkylation.

[0495] 21. An agent according to any of the preceding items, wherein the agent comprises or consists of tandem repeats comprising two or more repeat units.

[0496] 22. The agent according to item 21, wherein the repeating unit comprises or consists of an amino acid sequence of any one or more sequences as described in the preceding items.

[0497] 23. The agent according to any of the preceding items, wherein the agent is fused to another polypeptide.

[0498] 24. The agent according to item 20, wherein the polypeptide is selected from the group consisting of glutathione-S-transferase (GST) and protein A.

[0499] 25. The agent according to any of the preceding items, wherein the agent is fused to a tag.

[0500] 26. The agent according to item 25, wherein the tag is an oligohistidine tag.

[0501] 27. The agent according to any of the preceding items, wherein the agent is cyclic.

[0502] 28. The agent according to any of the preceding items, wherein the agent is capable of forming at least one intramolecular cysteine ​​bridge.

[0503] 29. An agent according to any of the preceding items, wherein the agent is a variant of a peptide, wherein the variant comprises or consists of a sequence in which any one amino acid has been changed to another proteinogenic or non-proteinogenic amino acid, provided that no more than five amino acids are so changed.

[0504] 30. The agent according to item 29, wherein the variant comprises or consists of a sequence in which no more than five amino acids are changed to another proteinogenic or non-proteinogenic amino acid, such as no more than 4 amino acids, such as no more than 3 amino acids, such as no more than 2 amino acids, such as no more than 1 amino acid is changed.

[0505] 31. An agent according to any of the preceding items, wherein one or more amino acids are conservatively substituted.

[0506] 32. The agent according to any of the preceding items, wherein the peptide comprises or consists of one or more additional amino acids inserted at the N- and / or C-terminus and / or within the sequence.

[0507] 33. The agent according to any of the preceding items, wherein the peptide has one additional amino acid.

[0508] 34. An agent according to any of the preceding items, wherein the agent further comprises a detectable portion.

[0509] 35. The agent according to item 34, wherein the detectable portion comprises or consists of a radioactive isotope.

[0510] 36. The agent according to item 35, wherein the radioisotope is selected from 99m Tc, 111 In, 67 Ga, 68 Ga, 72 As, 89 Zr, 123 I and 201 The group composed of Tl.

[0511] 37. The agent according to item 34, wherein the detectable moiety is detectable by imaging techniques such as SPECT, PET, MRI, optical or ultrasound imaging.

[0512] 38. A composition comprising a medicament according to any one of the preceding items.

[0513] 39. The composition according to item 38, wherein the composition is a pharmaceutical composition.

[0514] 40. The composition according to item 38, wherein the composition is a cosmetic composition.

[0515] 41. The composition according to any of the preceding items, wherein the composition is a coating.

[0516] 42. An implant comprising a medicament according to any one of the preceding items.

[0517] 43. The implant according to item 42, wherein said implant is coated with a composition comprising an agent according to any one of the preceding items.

[0518] 44. The implant according to item 42, wherein the implant is an implant of biomaterial.

[0519] 45. An implant according to item 44, wherein said biomaterial is bone.

[0520] 46. ​​The implant according to item 42, wherein said implant is a medical device.

[0521] 47. The implant according to item 46, wherein the medical device is a stent.

[0522] 48. The medicament according to any of the preceding items, for use in increasing angiogenesis in a subject.

[0523] 49. The agent according to any one of the preceding items, for use as an angiogenesis inducing agent.

[0524] 50. The medicament according to any of the preceding items, for use in improving myocyte survival in cardiovascular disease.

[0525] 51. The medicament according to any of the preceding items, for use in improving neuronal cell survival in cerebrovascular diseases.

[0526] 52. A medicament according to any of the preceding items for use in the treatment of a disease or condition associated with reduced or impaired angiogenesis.

[0527] 53. A method for inducing angiogenesis, the method comprising administering to a subject an agent according to any one of the preceding items.

[0528] 54. The medicament according to any one of the preceding items, for use in treating or preventing a disease or disorder in a subject, wherein the disease or disorder is selected from the group consisting of:

[0529] i. Diseases of the circulatory system,

[0530] ii. Damage caused by external factors,

[0531] iii. Diseases of the immune system,

[0532] iv. Diseases of the nervous system, and

[0533] v. Diseases of the musculoskeletal system or connective tissue.

[0534] 55. A medicament for use according to any one of the preceding items for the treatment or prevention of complications associated with a disease or condition selected from:

[0535] i. Diseases of the circulatory system,

[0536] ii. Damage caused by external factors,

[0537] iii. Diseases of the immune system,

[0538] iv. Circulatory system symptoms, signs or clinical findings,

[0539] v. Diseases of the myocardium or heart chambers, and

[0540] vi. Endocrine, nutritional or metabolic diseases.

[0541] 56. A medicament for use according to any one of the preceding items, wherein the disease of the circulatory system is selected from the group consisting of:

[0542] i.Ischemic heart disease,

[0543] ii. Cerebrovascular disease,

[0544] iii. Coronary artery disease,

[0545] iv. Diseases of arteries, arterioles or capillaries,

[0546] v. Circulatory system symptoms, signs or clinical findings,

[0547] vi. Diseases of the myocardium or heart chambers, and

[0548] vii. Endocrine, nutritional or metabolic diseases.

[0549] 57. The medicament for use according to any one of the preceding items, wherein the ischemic heart disease is selected from the group consisting of:

[0550] i. acute ischemic heart disease, such as myocardial infarction, such as acute myocardial infarction and unspecified acute ischemic heart disease (acute coronary syndrome),

[0551] ii. Chronic ischemic heart disease, such as other specific chronic ischemic heart disease (cardiovascular arteriosclerosis),

[0552] iii. Angina pectoris, such as unstable angina, and

[0553] iv. Obstructive arteriosclerosis.

[0554] 58. A medicament for use according to any one of the preceding items, wherein the myocardial infarction is ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI).

[0555] 59. A medicament for use according to any of the preceding items, wherein the presence of STEMI or NSTEMI is followed by certain current complications, for example within a period of 28 days.

[0556] 60. A medicament for use according to any one of the preceding items, wherein the disease of the circulatory system is cardiovascular sclerosis.

[0557] 61. A medicament for use according to any of the preceding items, wherein the disease of the circulatory system is or is associated with systemic sclerosis.

[0558] 62. The medicament for use according to any one of the preceding items, wherein the cerebrovascular disease is selected from the group consisting of:

[0559] i. Cerebral ischemia, such as ischemic stroke (stroke), such as cerebral infarction, and

[0560] ii. Asymptomatic stenosis of intracranial or extracranial arteries (cerebral arteriosclerosis).

[0561] 63. An agent for use according to any one of the preceding items, wherein the ischemic stroke is associated with a patient history of transient ischemic attack (TIA) or cerebral infarction without residual deficits.

[0562] 64. A medicament for use according to any one of the preceding items, wherein the ischemic stroke is associated with a patient's history of traumatic brain injury or sequelae of cerebrovascular disease.

[0563] 65. The medicament for use according to any one of the preceding items, wherein the cerebrovascular disease is selected from the group consisting of:

[0564] x. Non-traumatic subarachnoid hemorrhage,

[0565] xi. Non-traumatic intracerebral hemorrhage,

[0566] xii. Other and unspecified non-traumatic intracranial hemorrhage,

[0567] xiii. Cerebral infarction,

[0568] xiv. Occlusion and stenosis of the anterior cerebral artery without causing cerebral infarction,

[0569] xv. Occlusion and stenosis of cerebral arteries without causing cerebral infarction,

[0570] xvi. Other cerebrovascular diseases,

[0571] xvii. Cerebrovascular disorders associated with other diseases (cerebrovascular disorders classified elsewhere), and

[0572] xviii. Sequelae of cerebrovascular disease.

[0573] 66. A medicament for use according to any one of the preceding items, wherein the disease of the arteries, arterioles or capillaries is selected from the group consisting of:

[0574] i. Atherosclerosis,

[0575] ii. Aortic aneurysm and dissection,

[0576] iii. Other aneurysms,

[0577] iv. Other peripheral vascular diseases,

[0578] v. Arterial embolism and thrombosis,

[0579] vi. Atherosclerotic embolism,

[0580] vii. Septic arterial embolism,

[0581] viii. Other diseases of arteries and arterioles,

[0582] ix. Diseases of the capillaries, and

[0583] x. A disorder of the arteries, arterioles, or capillaries associated with another disease (a disorder of the arteries, arterioles, or capillaries classified under Diseases of Other Sites).

[0584] 67. A medicament for use according to any one of the preceding items, wherein the disease of the arteries, arterioles or capillaries is a chronic arterial occlusive disease, such as atherosclerotic chronic arterial occlusive disease or vascular sclerosis.

[0585] 68. A medicament for use according to any one of the preceding items, wherein the circulatory symptom, sign or clinical finding is a symptom or sign involving the circulatory system, such as an undiagnosed abnormal blood pressure reading, such as cardiac arrest.

[0586] 69. A medicament for use according to any of the preceding items, wherein the disease of the myocardium or heart chambers is a cardiomyopathy, such as dilated cardiomyopathy.

[0587] 70. A medicament for use according to any of the preceding items, wherein the disease of the immune system is a non-organ specific systemic autoimmune disorder, such as a vasculitis, such as thromboangiitis obliterans (Buerger's disease).

[0588] 71. A medicament for use according to any one of the preceding items, wherein the disease of the nervous system is selected from the group consisting of:

[0589] i. Movement disorders, such as Parkinson's syndrome, such as Parkinson's disease,

[0590] ii. Multiple sclerosis or other white matter disorders, such as multiple sclerosis, and

[0591] iii. Conditions with neurocognitive impairment as a predominant feature, such as Alzheimer's disease.

[0592] 72. A medicament for use according to any of the preceding items, wherein the disease of the musculoskeletal system or connective tissue is a condition related to the spine, such as a herniated disc.

[0593] 73. A medicament for use according to any of the preceding items, wherein the disease of the circulatory system, the disease of the immune system, the disease of the nervous system, or the disease of the musculoskeletal system or connective tissue is or is associated with diabetes.

[0594] 74. A medicament for use according to any one of the preceding items, wherein the diabetes is selected from type 1 diabetes and type 2 diabetes.

[0595] 75. A medicament for use according to any one of the preceding items, wherein the subject suffers from diabetes.

[0596] 76. A medicament for use according to any one of the preceding items, wherein the subject is a mammal.

[0597] 77. A medicament for use according to item 76, wherein the mammal is a human.

[0598] 78. A method for treating or preventing a disease or condition in a subject, wherein the disease or condition is selected from the group consisting of:

[0599] i. Diseases of the circulatory system,

[0600] ii. Damage caused by external factors,

[0601] iii. Diseases of the immune system,

[0602] iv. Diseases of the nervous system, and

[0603] v. Diseases of the musculoskeletal system or connective tissue,

[0604] The method comprises administering to a subject in need thereof a therapeutically effective amount of an agent according to any one of the preceding items.

[0605] 79. Use of the agent according to any one of the preceding items for the manufacture of a medicament for the treatment or prevention of a disease or condition selected from the group consisting of:

[0606] i. Diseases of the circulatory system,

[0607] ii. Damage caused by external factors,

[0608] iii. Diseases of the immune system,

[0609] iv. Diseases of the nervous system, and

[0610] v. Diseases of the musculoskeletal system or connective tissue.

[0611] 80. An agent according to any of the preceding items for use in improving post-operative vascularization.

[0612] 81. A medicament for use according to any of the preceding items, wherein the surgery is a surgery of the cardiovascular system.

[0613] 82. A medicament for use according to any of the preceding items, wherein the surgery on the cardiovascular system is a vascular transplant.

[0614] 83. A medicament according to any of the preceding items for use in increasing angiogenesis in a subject having an implant.

[0615] 84. A medicament for use according to any of the preceding items, wherein the implant is an implant of a biomaterial.

[0616] 85. A medicament for use according to any of the preceding items, wherein the biomaterial is bone.

[0617] 86. A medicament for use according to any of the preceding items, wherein the implant is a medical device.

[0618] 87. A medicament for use according to any one of the preceding items, wherein the medical device is a stent.

[0619] 88. An agent according to any of the preceding items for use in increasing angiogenesis in a subject undergoing or having undergone a transplant.

[0620] 89. A medicament for use according to any one of the preceding items, wherein the transplant is a transplant of an organ, tissue or cell.

[0621] 90. A medicament for use according to any one of the preceding items, wherein the transplantation of said cells is a transplantation of bone marrow cells.

[0622] 91. A medicament for use according to any one of the preceding items, wherein the transplantation of the organ is a transplantation of heart or cardiovascular tissue.

[0623] Example

[0624] Example 1: Polypeptides of the present disclosure stimulate proliferation of endothelial cells and vascular smooth muscle cells

[0625] method

[0626] Cell proliferation was assessed using BrdU cell proliferation Elisa kit (Abcam, UK). After incubation overnight with each complete medium at 37°C, HUVEC and HCASMC on 96-well plates were directly transfected with siRNA / siRNA-NC for NRP-1 knockdown-related experiments; for test polypeptide stimulation, HUVEC and HCASMC were starved for another 24 hours and 48 hours with low serum conditions before treatment. 32 hours after transfection or polypeptide stimulation, cells were cultured with BrdU reagent for another 16 hours to determine cell proliferation. Subsequent steps were performed according to the manufacturer's instructions and data were read by Wallac 1420Victor2 (Perkin Elmer, USA).

[0627] For stimulation of endothelial cell proliferation, human umbilical cord endothelial cells were first treated with scrambled noncoding siRNA (NC) or siRNA against NRP-1, then they were treated with FOL26 at concentrations of 10 nM, 100 nM, and 1000 nM, and DNA synthesis was analyzed by measuring BrdU uptake.

[0628] result

[0629] The results for FOL26 are shown in Figure 1 and for FOL56 shown in Fig.11 Both tested polypeptides induced a significant increase in the proliferation of HUVECs and HCASMCs.

[0630] FOL26 stimulation of endothelial cell proliferation is NRP-1 dependent ( Figure 8 ).

[0631] in conclusion

[0632] The polypeptides of the present disclosure stimulate proliferation of endothelial cells and vascular smooth muscle cells.

[0633] Example 2: Polypeptides of the Disclosure Induce Tube Formation in HUVECs

[0634] method

[0635] As described above, cells were transfected for 48 hours or starved for 24 hours with 0.5% supplement on 6-well plates and detached by Accutase (Gibco, USA) to obtain cell suspensions. Geltrex reduced growth factor basement membrane matrix ((Invitrogen, CA, USA) was thawed overnight at 4°C and then added to a 96-well plate (50 μl / well). The coated 96-well plate was placed in an incubator for more than 30 minutes for further use, and the cell suspension was seeded therein at a density of 1.5×104 / well. For NRP-1 silencing experiments, cells were cultured with complete medium. For peptide treatment experiments, cells were stimulated with complete medium plus different concentrations of peptides. For NRP-1 rescue experiments, cells transfected with siRNA were cultured with complete medium and NRP-1 stimulation. After 24 hours of incubation, images were recorded by an inverted microscope (Nikon, EclipseTE2000-U, Japan), and the total length (pixel / unit) of the main segment of the blood vessels in each image was quantified using the angiogenesis analyzer plug-in ImageJ software program. Data were analyzed using photos from 8-14 wells / condition.

[0636] Human umbilical cord endothelial cells were first treated with scrambled noncoding siRNA (NC) or siRNA against NRP-1, followed by treatment with FOL26 at concentrations of 10 nM, 100 nM, and 1000 nM, and endothelial tube formation and total primary segments were measured using Image J. Gene expression of PECAM-1 (CD31) was analyzed.

[0637] result

[0638] The results for FOL26 are shown in Figure 2 and for FOL56 shown in Fig.12 The tested polypeptide significantly increased tube formation in HUVECs. The polypeptide also increased the expression of PECAM-1. Fig.10 It was shown that FOL26 increased tube formation compared to controls in an NRP-1-dependent manner.

[0639] in conclusion

[0640] The polypeptides of the present disclosure induce tube formation in HUVECs.

[0641] Example 4: Polypeptides of the Disclosure Prevent Apoptosis in HUVECs and HCASMCs

[0642] method

[0643] Human umbilical vein endothelial cells (HUVEC) and human coronary artery smooth muscle cells (HCASMC) were purchased from ThermoFisher. Cells were grown in medium 200 containing 2% low serum growth supplement and medium 231 with 5% smooth muscle growth supplement (Invitrogen, CA, USA) supplemented with antibiotic-antimycotic (1%, Invitrogen, CA, USA). Test polypeptides and sFasL (PeproTech, NJ, USA) were dissolved in their respective complete culture media.

[0644] Caspase-Glo 3 / 7 assay (Promega, USA) is performed to assess apoptosis. HUVEC and HCASMC are seeded into 96-well plates at a density of 3-5x 103 / well. For other NRP-1 on cells transfected with siRNA, NRP-1 is added 24 hours after transfection, and a mixture of Caspase-Glo 3 / 7 is added 48 hours after polypeptide stimulation. Subsequent steps are performed using FOL26 and FOL56 as test compounds according to the manufacturer's instructions. Data are read by Wallac 1420Victor 2 (Perkin Elmer, USA).

[0645] result

[0646] For both HUVEC and HCASMC, the results are shown for FOL26. Figure 3 and for FOL56 shown in Fig.13 Both peptides reduced sFasL-induced apoptosis in the cell lines.

[0647] in conclusion

[0648] The polypeptides of the present disclosure prevent apoptosis in HUVECs and HCASMCs.

[0649] Example 5: Effects of the polypeptides of the present disclosure on gene expression in HUVEC and HCASMC

[0650] method

[0651] The cells on the 6-well plate were washed with cold DPBS (Gibco, USA) and homogenized in Trizol reagent (Invitrogen, CA, USA). Total RNA was extracted using PureLink RNA Extraction Kit (Invitrogen, CA, USA), followed by nucleic acid quantification using NanoDrop 2000c (Thermo Fisher Scientific, USA). In order to determine the mRNA expression of the target gene, real-time qPCR was performed using KAPA SYBR Quick One-Step qRT-PCR Premix Kit (KAPA Biosystems, USA) on the LightCycler 480 system (Roche, Mannheim, Germany). All primers were purchased from miScript Primer Assays (Qiagen, Valencia, CA), and the GAPDH mRNA expression of each sample was used for standardization. The cells on the 6-well plate were washed with cold DPBS, and lysed on ice with a mixture of lysis buffer and protease inhibitors, then centrifuged at 4 ° C for 20 minutes at 15,000 g. The supernatant was measured for protein concentration using a BCA protein assay kit (Thermo Fisher Scientific, USA). The protein samples were loaded onto SDS-PAGE gels and separated by electrophoresis and subsequently transferred to PVDF membranes (Millipore, USA). The membranes were blocked with 5% skim milk. Primary antibodies (Abcam, UK) and secondary antibodies were incubated with the membranes overnight at 4°C and at room temperature for 1 hour.

[0652] result

[0653] The results for FOL26 are shown in Figure 4-7 and for FOL56 shown in Figure 14-17 Table 1 shows various important biological mediators in the process of tissue regeneration.

[0654] Table 1: Growth factors and cytokines that influence various steps in tissue regeneration.

[0655] Monocyte chemotaxis PDGF, FGF, TGF-β Fibroblast migration PDGF, EGF, FGF, TGF-β, TNF, IL-1 Fibroblast proliferation PDGF, EGF, FGF, TNF Angiogenesis VEGF, Ang, FGF Collagen synthesis TGF-β、PDGF Collagenase secretion PDGF, EGF, FGF, TNF, TGF-β inhibition

[0656] in conclusion

[0657] The polypeptides of the present disclosure induce an environment that induces tissue regeneration through TNF and IL-6 expression, most likely promoting fibroblast migration and proliferation, collagen secretion, angiogenesis, and inducing proper tissue regeneration by inducing cellular remodeling through MMP expression.

[0658] Example 6. Effects of FOL-026 peptide on endothelial cell function and gene expression.

[0659] method

[0660] The effects of FOL-026 peptide on the proliferation of human umbilical vascular endothelial cells (HUVEC) were determined by BrdU uptake (n=8-9 / group) and active caspase-3 / -7 (n=7-10 / group), respectively. Fig.18 a) and apoptosis induced by hypoxia ( Fig.18 c). The ROS levels in cells pre-incubated with FOL-026 peptide and activated by 50ug / ml oxidized low-density lipoprotein (oxLDL) for 2 hours were evaluated using H2O2 measurement (n=4-8 / group). Fig.18 b) Representative images showing endothelial cell migration into scratch wounds in vitro ( Fig.19 a), and the wound closure rate in HUVECs stimulated with increasing concentrations of FOL-026 peptide was quantified by image J software ( Fig.19 b) (n=8-9 / group). Scale bar=150 um. Data are presented as mean±SEM and obtained from 3 to 4 independent replicates. *P<0.05, **P<0.01, ****P<0.0001 by one-way ANOVA and Dunnett's post hoc test.

[0661] result

[0662] Fig.18 The results shown in a indicate that the proliferation of human umbilical cord endothelial cells increased with the addition of FOL-026 peptide. FOL-026 also alleviated the effects of hypoxia-induced apoptosis in HUVECs and could reduce the amount of ROS levels induced by oxLDL ( Fig.18 c and 18b).

[0663] Fig.19 a and 19b show that the addition of FOL-026 accelerated HUVEC wound closure.

[0664] in conclusion

[0665] FOL-026 peptide has a stimulatory effect on the proliferation of endothelial cells.

[0666] Example 7. Effects of FOL-026 peptide on angiogenesis in vitro and in vivo

[0667] method

[0668] Representative images of tube formation in HUVECs treated with FOL-026 peptide are shown in Fig. 20 a. Total execution length ( Fig. 20 b) Total main section length ( Fig. 20 c) Total branch length ( Fig. 20 d) and total segment length ( Fig. 20 e) quantitative measurement to assess in vitro angiogenesis (for Fig.29 CD31+ positive area was used to evaluate the quantification of vascular density ( Fig.21 a, n=13 / group). Western blot analysis of phosphorylated AKT (pAKT-T308), AKT, phosphorylated ERK1 / 2 (p-ERK1 / 2), and ERK1 / 2 in endothelial cells stimulated with FOL-26 peptide for 48 hours ( Fig.21 b). Quantification of phosphorylation intensity was normalized to the respective total expression ( Fig.21 cd, n=3 / group).

[0669] Data are presented as mean ± SEM and were obtained from 3 to 4 independent replicates. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by one-way ANOVA and Dunnett's post hoc test.

[0670] result

[0671] Fig. 20 ad shows the positive effect of FOL-026 on tube formation. It demonstrates the increased vascular density effect of FOL-026 and how FOL-026 induces upregulation of angiogenesis-related genes.

[0672] in conclusion

[0673] The FOL-026 peptide affects angiogenesis both in vitro and in vivo.

[0674] Example 8: Effect of NRP-1 knockdown on endothelial cell function induced by FOL-026 peptide

[0675] method

[0676] The efficiency of small interfering RNA transfection in HUVECs for 48 h was confirmed by qRT-PCR (n=4) ( Fig. 22 a). Effects of FOL-026 peptide stimulation on cell proliferation in HUVECs transfected with siRNA-NC or siNRP-1 were assessed by BrdU incorporation (n=4-7 / group) and active caspase-3 / -7 (n=4-7 / group). Fig. 22b) and apoptosis under 0.1% oxygen ( Fig. 22 c). Representative images of endothelial cells at 0 and 5 hours after wounding are shown in 23a. The wound closure rate of HUVECs transfected with siRNA-NC / siNRP-1 stimulated with increasing concentrations of FOL-026 peptide was quantified by image J software ( Fig.23 b) (n = 9-12 / group). Scale bar = 150 um. Data are presented as mean ± SEM and are obtained from 3 to 4 independent replicates. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by Student's t-test for A and by two-way ANOVA followed by Sidak's and Dunnett's multiple comparison tests for B, C and E.

[0677] result

[0678] Fig. 22 ac shows that reducing NRP-1 expression blocks the effect of FOL-026

[0679] Fig.23 ab show that FOL-026 has a positive effect on wound closure in siRNA-NC / siNRP-1 transfected HUVECs.

[0680] in conclusion

[0681] FOL-026 stimulates wound closure in HUVECs by binding to NRP-1

[0682] Example 9: Effect of NRP-1 knockdown on tube formation induced by FOL-026 peptide

[0683] method

[0684] The tube formation in the siRNA-NC or siNRP-1 groups with increasing doses of FOL-026 peptide treatment was calculated using the Angiogenesis Analyzer plugin for ImageJ. Fig.24 a) and total length ( Fig.24 b) Total main section length ( Fig.24 c) Total branch length ( Fig.24 d) and total segment length ( Fig.24 e) (n=7-12 / group). Scale bar=150 um. Data are presented as mean±SEM and were obtained from 3 to 4 independent replicates. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 by two-way ANOVA followed by Sidak's and Dunnett's multiple comparison test.

[0685] Results and Conclusions

[0686] FOL-026 peptide induced tube formation in siRNA-NC and siNRP-1.

[0687] Example 10: Effect of FOL-026 peptide on smooth muscle cell function

[0688] method

[0689] The effects of FOL-026 peptide treatment on smooth muscle cell proliferation were evaluated by BrdU uptake (n=10 / group) and active caspase-3 / -7 (n=6-8 / group). Fig.25 a) and apoptosis induced by hypoxia ( Fig.25 c). H2O2 measurement of smooth muscle cells pre-incubated with FOL-26 peptide after 2 hours of stimulation with 50ug / ml oxidized low-density lipoprotein (oxLDL) ( Fig.25 b) (n=6-7 / group). Representative images of in vitro scratch wound assay are shown in ( Fig.26 a), and the wound healing ability of human coronary artery smooth muscle cells (HCASMC) treated with FOL-026 peptide was measured by image J software ( Fig.26 b) (n=10 / group). Scale bar=150 um. Data are presented as mean±SEM and obtained from 3 to 4 independent replicates. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 by one-way ANOVA and Dunnett's post hoc test.

[0690] Results and Conclusions

[0691] FOL-026 induces smooth muscle cell proliferation, inhibits apoptosis, reduces ROS formation and accelerates wound healing

[0692] Example 11: Effect of NRP-1 knockdown on smooth muscle cell function induced by FOL-026 peptide

[0693] method

[0694] qRT-PCR analysis of NRP-1 mRNA expression in HCASMCs transfected with small interfering RNA for 48 hours (n=4) ( Fig. 27 a). BrdU incorporation in HUVECs transfected with siRNA-NC / siNRP-1 treated with indicated concentrations of FOL-026 peptide ( Fig. 27 b, n = 10-11) and caspase-3 / -7 activation ( Fig. 27c, n = 3-10). Representative images of smooth muscle cells at 0 and 5 hours after scratching are shown in Fig.28 a. The wound closure rate of HCASMCs in the siRNA-NC and siNRP-1 groups stimulated with increasing concentrations of FOL-026 peptide was quantified by image J software ( Fig.28 b) (n=9-12 / group). Scale bar=150 um. Data are presented as mean ± SEM and are obtained from 3 to 4 independent replicates. For A, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 by Student's t-test, two-way ANOVA followed by Sidak's and Dunnett's multiple comparison test.

[0695] Results and Conclusions

[0696] FOL-026 has a positive effect on wound closure in siRNA-NC / siNRP-1-transfected HUVECs.

[0697] Example 12: FOL-005 peptide stimulates endothelial cell and smooth muscle cell proliferation and wound healing ability

[0698] method

[0699] Endothelial cell proliferation was assessed by BrdU uptake in human umbilical vascular endothelial cells (HUVEC) stimulated with increasing concentrations of FOL-005 peptide for 48 h. Fig.29 a) (n=7-10 / group).

[0700] The wound closure rate in HUVECs treated with the indicated doses of FOL-005 was quantified by image J software ( Fig.29 b) (n=12-14 / group), and representative images at 0 and 6 hours after scratching are shown ( Fig.29 c).

[0701] The effect of FOL-005 peptide on smooth muscle cell proliferation was determined by BrdU incorporation in peptide-treated human coronary artery smooth muscle cells (HCASMC). Fig.30 a). Scratch wound assay of HCASMC incubated with FOL-005 peptide for 5 hours was measured by image J software ( Fig.30 b) (n=10-12 / group), and shows representative images of smooth muscle cells migrating into scratches in vitro ( Fig.30c). Scale bar = 150 um. Data are presented as mean ± SEM and were obtained from 3 to 4 independent replicates. p values ​​are shown and calculated using one-way ANOVA and Dunnett's post hoc test.

[0702] result

[0703] Fig.29 The results shown in a indicate that the proliferation of human umbilical vascular endothelial cells (HUVECs) increased with the addition of the FOL-005 peptide. Fig.29 The scratch wound assays in b and 29c indicated that the FOL-005 peptide accelerated HUVEC wound closure.

[0704] Fig.30 The results shown in a indicate that the proliferation of human coronary artery smooth muscle cells (HCASMC) is increased with the addition of FOL-005 peptide.

[0705] Fig.30 The scratch wound assays in b and 30c indicated that the FOL-005 peptide accelerated HCASMC wound closure.

[0706] in conclusion

[0707] The FOL-005 peptide has positive effects on endothelial cell and smooth muscle cell proliferation and wound healing ability.

[0708] Example 13: Effect of FOL-005 peptide on tube formation

[0709] method

[0710] Tube formation in human umbilical vascular endothelial cells (HUVECs) treated with FOL-005 peptide was shown in Fig.31 a. Fig.31 b Quantitative measurement of total main segment length for assessment of in vitro angiogenesis (n=7 / group). Scale bar=150 um. Data are presented as mean±SEM and obtained from 3 to 4 independent replicates. p values ​​are shown and calculated using one-way ANOVA and Dunnett's post hoc test in B, two-way ANOVA followed by Sidak's and Dunnett's multiple comparison tests.

[0711] result

[0712] Fig.31 The results shown in a and 31b indicate that the addition of FOL-005 peptide increased tube formation in human umbilical vascular endothelial cells (HUVECs)

[0713] in conclusion

[0714] The addition of FOL-005 peptide had a stimulatory effect on endothelial cell tube formation.

[0715] Sequence Overview

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723] References

[0724] Gottrup F., A specialized wound-healing center concept:importance of a multidisciplinary department structure and surgical treatment facilities in the treatment of chronic wounds. The American Journal of Surgery. 2004; 187(5):S38-S43.

[0725] Kirker KR, James GA, In vitro studies evaluating the effects of biofilms on wound-healing cells: a review.APMIS.2017;125(4):344-52.

[0726] Frykberg RG, Banks J., Challenges in the Treatment of Chronic Wounds. Adv Wound Care (New Rochelle). 2015; 4(9):560-82.

Claims

1. A medicament comprising: a) a peptide selected from the group consisting of: (i) a peptide comprising or consisting of an amino acid sequence of the following general formula: X5X6SX7X8YGLR (SEQ ID NO: 1) in: X5 is D or G; X6 is I or G; X7 is V or L; X8 is V or A; (ii) a peptide comprising or consisting of an amino acid sequence of the following general formula: X 14 LX 15 YGIK(SEQ ID NO:105) in: X 14 is E or G; X 15 is S or T; (iii) a peptide comprising or consisting of an amino acid sequence selected from the group consisting of: VDTYDGDISVVYGL(SEQ ID NO:34), VDTYDGDISVVYG(SEQ ID NO:35), VDTYDGDISVVY (SEQ ID NO: 36), VDTYDGDISVV (SEQ ID NO: 37), VDTYDGDISV (SEQ ID NO: 38), VDTYDGDIS (SEQ ID NO: 39), VDTYDGRGDSVVYGLR(SEQ ID NO:40), VDVPNGDISLAYGL(SEQ ID NO:41), VDVPNGDISLAYG(SEQ ID NO:42), VDVPNGDISLA (SEQ ID NO: 43), VDVPNGDIS (SEQ ID NO: 44), GDPNDGRGDSVVYGLR(SEQ ID NO:45), LDGLVRAYDNISPVG(SEQ ID NO:46), GDPNGDISVVYGLR (SEQ ID NO: 47) VDVPNGDISLAYRLR(SEQ ID NO:48), VDVPEGDISLAYRLR(SEQ ID NO:49), V(beta-D)TYDGDISVVYGLR(SEQ ID NO:50), VDTY(beta-D)GDISVVYGLR(SEQ ID NO:51), VDTYDG(beta-D)ISVVYGLR(SEQ ID NO:52); CLAEIDSC (circular) (SEQ ID NO: 130), CFKPLAEIDSIECSYGIK(cyclic) (SEQ ID NO: 131), cyclic CFKPLAEIDSIEC (SEQ ID NO: 132), KPLAEIDSIELSYGI(SEQ ID NO:133), KPLAEIDSIELSYG(SEQ ID NO:134), KPLAEIDSIELSY(SEQ ID NO:135), KPLAEIDSIELS(SEQ ID NO:136), KPLAEIDSIEL (SEQ ID NO: 137), and KPLAEIDSIE (SEQ ID NO: 138); b) a polynucleotide which, when expressed, encodes the peptide of a); c) a vector comprising the polynucleotide of b); or d) a cell comprising the polynucleotide of b) or the vector of c), It is used for treating and / or preventing a disease or condition associated with reduced or impaired angiogenesis in a subject.

2. A medicament for use according to claim 1, wherein the peptide comprises an amino acid sequence of the following general formula: VDX2X3X4GX5X6SX7X8YGLR(SEQ ID NO:2) in: X2 is T or V; X3 is Y or P; X4 is D or N; X5 is D or G; X6 is I or G; X7 is V or L; and X8 is V or A.

3. A medicament for use according to any one of the preceding claims, wherein the peptide comprises an amino acid sequence of the following general formula: VDTYX4GX5X6SX7X8YGLR(SEQ ID NO:3) in: X4 is D or N; X5 is D or G; X6 is I or G; X7 is V or L; and X8 is V or A.

4. A medicament for use according to any one of the preceding claims, wherein the peptide comprises an amino acid sequence of the following general formula: VDTYDGZ7Z8SZ 10 WITH 11 YGLR(SEQ ID NO:4) in: X5 is D or G; X6 is I or G; X7 is V or L; and X8 is V or A.

5. A medicament for use according to any one of the preceding claims, wherein the peptide comprises an amino acid sequence of the following general formula: VDTYDGZ7Z8SVVYGLR(SEQ ID NO:5) in: X5 is D or G; and X6 is I or G.

6. A medicament for use according to claim 1, wherein the peptide comprises an amino acid sequence of the following general formula: KX9LAX 10 X 11 X 12 X 13 IX 14 LX 15 YGIK(SEQ ID NO:106) in: X9 is C, P or G; X 10 is E or G; X 11 is C, D or I; X 12 is D, I, S or G; X 13 is S, D or G; X 14 is E or G; and X 15 It is S or T.

7. A medicament for use according to claim 1, wherein the peptide comprises an amino acid sequence of the following general formula: KX9LAX 10 X 11 X 12 X 13 IX 14 LSYGIK(SEQ ID NO:107) in: X9 is C, P or G; X 10 is E or G; X 11 is C, I, or absent; X 12 is D, G or not present; X 13 is S, G, or absent; and X 14 It is E or G.

8. A medicament for use according to claim 1, wherein the peptide comprises an amino acid sequence of the following general formula: KX9LAX 10 IX 14 LSYGIK(SEQ ID NO:108) in: X9 is C, P or G; X 10 is E or G; and X 14 It is E or G.

9. The medicament for use according to claim 1, wherein the peptide comprises the amino acid sequence IELSYGIK (SEQ ID NO: 109).

10. A medicament for use according to claim 1, provided that if X 14 is T, then the peptide contains no more than 25 amino acid residues.

11. The medicament for use according to claim 1, wherein the peptide comprises or consists of an amino acid sequence selected from the group consisting of: VDTYDGGISVVYGLR(SEQ ID NO:6), VDTYDGDISVVYGLR(SEQ ID NO:7), DTYDGDISVVYGLR(SEQ ID NO:8), TYDGDISVVYGLRS(SEQ ID NO:9), TYDGDISVVYGLR(SEQ ID NO:10), YDGDISVVYGLRS(SEQ ID NO:11), YDGDISVVYGLR (SEQ ID NO: 12), DGDISVVYGLRS (SEQ ID NO: 13), DGDISVVYGLR (SEQ ID NO: 14), GDISVVYGLRS (SEQ ID NO:15), GDISVVYGLR (SEQ ID NO:16), DISVVYGLRS (SEQ ID NO:17), DISVVYGLR (SEQ ID NO:18), VDVPNGDISLAYGLR (SEQ ID NO:19), DVPNGDISLAYGLRS (SEQ ID NO:20), DVPNGDISLAYGLR (SEQ ID NO:21), VPNGDISLAYGLRS (SEQ ID NO:22), VPNGDISLAYGLR (SEQ ID NO:23), PNGDISLAYGLRS (SEQ ID NO:24), PNGDISLAYGLR (SEQ ID NO:25), NGDISLAYGLRS (SEQ ID NO:26), NGDISLAYGLR (SEQ ID NO:27), GDISLAYGLRS (SEQ ID NO:28), GDISLAYGLR (SEQ ID NO:29), DISLAYGLRS (SEQ ID NO:30), DISLAYGLR (SEQ ID NO:31), VDTYDGDGSVVYGLR (SEQ ID NO:32), VDVPEGDISLAYGLR (SEQ ID NO:33). AEIDSIELSYGIK (SEQ ID NO:110), KPLAEIDSIELSYGIK (SEQ ID NO:111), KCLAECDSIELSYGIK (circular) (SEQ ID NO:112), KPLAEDISIELSYGIK (SEQ ID NO:113), KPLAEISDIELSYGIK (SEQ ID NO:114), KPLAEIGDIELSYGIK (SEQ ID NO:115), KPLAEGDIELSYGIK (SEQ ID NO:116), KPLAEIELSYGIK (SEQ ID NO:117), KPLAEIDSIELTYGIK (SEQ ID NO:118), KPLAEIDGIELSYGIK (SEQ ID NO:119), KPLAEIDGIELTYGIK (SEQ ID NO:120), KPLAEIGSIELSYGIK (SEQ ID NO:121), KGLAEIDSIELSYGIK (SEQ ID NO:122), KPLAGIDSIGLSYGIK (SEQ ID NO:123), circular KCLAEIDSCELSYGIK (SEQ ID NO:124), LAEIDSIELSYGIK(SEQ ID NO:125), EIDSIELSYGIK(SEQ ID NO:126), IDSIELSYGIK (SEQ ID NO: 127), DSIELSYGIK (SEQ ID NO: 128), SIELSYGIK (SEQ ID NO: 129), and IELSYGIK (SEQ ID NO: 109).

12. The medicament for use according to claim 1, wherein the peptide comprises or consists of the amino acid sequence VDTYDGGISVVYGLR (SEQ ID NO: 6).

13. The medicament for use according to claim 1, wherein the peptide comprises or consists of the amino acid sequence VDTYDGDISVVYGLR (SEQ ID NO: 7).

14. The medicament for use according to claim 1, wherein the peptide comprises or consists of the amino acid sequence AEIDSIELSYGIK (SEQ ID NO: 110).

15. An agent for use according to any one of the preceding claims, wherein the peptide comprises no more than 85 amino acids, such as no more than 80 amino acids, such as no more than 75 amino acids, such as no more than 70 amino acids, such as no more than 65 amino acids, such as no more than 60 amino acids, such as no more than 55 amino acids, such as no more than 50 amino acids, such as no more than 55 amino acids, such as no more than 40 amino acids, such as no more than 35 amino acids, such as no more than 30 amino acids, such as no more than 28 amino acids, such as no more than 26 amino acids, such as no more than 24 amino acids, such as no more than 22 amino acids, such as no more than 20 amino acids, such as no more than 19 amino acids, such as no more than 18 amino acids, such as no more than 17 amino acids, such as no more than 16 amino acids, such as no more than 15 amino acids, such as no more than 14 amino acids, such as no more than 13 amino acids, such as no more than 12 amino acids, such as no more than 11 amino acids, such as no more than 10 amino acids.

16. An agent for use according to any one of the preceding claims, wherein the peptide comprises at least 2 additional amino acids, such as at least 3, such as at least 4, such as at least 5, such as at least 6, such as at least 7, such as at least 8, such as at least 9, such as at least 10, such as at least 15 or such as at least 20 additional amino acids conjugated to the N- or C-terminus of the peptide.

17. An agent for use according to any one of the preceding claims, wherein the agent is non-naturally occurring.

18. An agent for use according to any one of the preceding claims, wherein the agent is conjugated to a moiety.

19. The medicament for use according to claim 15, wherein the moiety is selected from the group consisting of polyethylene glycol (PEG), a monosaccharide, a fluorophore, a chromophore, a radioactive compound and a cell penetrating peptide.

20. A medicament for use according to any one of the preceding claims, wherein the medicament is further modified, for example by glycosylation, pegylation, amidation, esterification, acylation, acetylation and / or alkylation.

21. A medicament for use according to any one of the preceding claims, wherein the medicament comprises or consists of a tandem repeat comprising two or more repeat units.

22. A medicament for use according to claim 21, wherein the repeating unit comprises or consists of an amino acid sequence of any one or more of the sequences as described in the preceding claims.

23. An agent for use according to any one of the preceding claims, wherein the agent is fused to another polypeptide.

24. The agent for use according to claim 23, wherein the polypeptide is selected from the group consisting of glutathione-S-transferase (GST) and protein A.

25. A medicament for use according to any one of the preceding claims, wherein the medicament is fused to a label.

26. The medicament for use according to claim 25, wherein the tag is an oligohistidine tag.

27. A medicament for use according to any one of the preceding claims, wherein the medicament is cyclic.

28. An agent for use according to any one of the preceding claims, wherein the agent is capable of forming at least one intramolecular cysteine ​​bridge.

29. An agent for use according to any one of the preceding claims, wherein the agent is a variant of a peptide, wherein the variant comprises a sequence in which any one amino acid has been changed to another proteinogenic amino acid or a non-proteinogenic amino acid, provided that no more than five amino acids are so changed, or consists of said sequence.

30. An agent for use according to claim 29, wherein the variant comprises or consists of a sequence in which no more than five amino acids are changed to another proteinogenic amino acid or a non-proteinogenic amino acid, such as no more than 4 amino acids, such as no more than 3 amino acids, such as no more than 2 amino acids, such as no more than 1 amino acid is changed.

31. A medicament for use according to any one of the preceding claims, wherein one or more amino acids are conservatively substituted.

32. A medicament for use according to any one of the preceding claims, wherein the peptide comprises or consists of one or more additional amino acids inserted at the N- and / or C-terminus and / or within the sequence.

33. A medicament for use according to any one of the preceding claims, wherein the peptide has one additional amino acid.

34. A medicament for use according to any one of the preceding claims, wherein the medicament further comprises a detectable moiety.

35. A medicament for use according to any one of the preceding claims, wherein the medicament is in a composition.

36. A medicament for use according to claim 35, wherein the composition is a pharmaceutical composition.

37. A medicament for use according to claim 35, wherein the composition is a cosmetic composition.

38. A medicament for use according to any one of the preceding claims, wherein the composition is a coating.

39. A medicament for use according to any one of claims 35 to 38, wherein the composition is a coating for an implant.

40. A medicament for use according to claim 39, wherein the implant is an implant of a biomaterial.

41. A medicament for use according to claim 40, wherein the biological material is bone.

42. A medicament for use according to claim 39, wherein the implant is a medical device.

43. A medicament for use according to claim 42, wherein the medical device is a stent.

44. An agent for use according to any one of the preceding claims, wherein the agent increases angiogenesis in a subject.

45. A medicament for use according to any one of the preceding claims, wherein the medicament is an angiogenesis inducing agent.

46. ​​A medicament for use according to any one of the preceding claims, wherein the medicament is capable of improving myocyte survival in cardiovascular disease.

47. A medicament for use according to any one of the preceding claims, wherein the medicament is capable of improving neuronal cell survival in cerebrovascular disease.

48. A medicament for use according to any one of the preceding claims, wherein the disease or condition is selected from the group consisting of: i. Diseases of the circulatory system, ii. Damage caused by external factors, iii. Diseases of the immune system, iv. Diseases of the nervous system, and v. Diseases of the musculoskeletal system or connective tissue.

49. The medicament for use according to claim 48, wherein the disease of the circulatory system is selected from the group consisting of: i.Ischemic heart disease, ii. Cerebrovascular disease, iii. Coronary artery disease, iv. Diseases of arteries, arterioles or capillaries, v. Circulatory system symptoms, signs or clinical findings, vi. Diseases of the myocardium or heart chambers, and vii. Endocrine, nutritional or metabolic diseases.

50. The medicament for use according to claim 49, wherein the ischemic heart disease is selected from the group consisting of: i. acute ischemic heart disease, such as myocardial infarction, such as acute myocardial infarction and unspecified acute ischemic heart disease (acute coronary syndrome), ii. Chronic ischemic heart disease, such as other specific chronic ischemic heart disease (cardiovascular arteriosclerosis), iii. Angina pectoris, such as unstable angina, and iv. Obstructive arteriosclerosis.

51. A medicament for use according to claim 50, wherein the myocardial infarction is ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI).

52. A medicament for use according to claim 51, wherein the presence of STEMI or NSTEMI is followed by certain current complications, for example within a period of 28 days.

53. A medicament for use according to claim 48, wherein the disease of the circulatory system is cardiovascular sclerosis.

54. A medicament for use according to claim 48, wherein the disease of the circulatory system is or is associated with systemic sclerosis.

55. The medicament for use according to claim 49, wherein the cerebrovascular disease is selected from the group consisting of: i. Cerebral ischemia, such as ischemic stroke (stroke), such as cerebral infarction, and ii. Asymptomatic stenosis of intracranial or extracranial arteries (cerebral arteriosclerosis).

56. The medicament for use according to claim 55, wherein the ischemic stroke is associated with a patient history of transient ischemic attack (TIA) or cerebral infarction without residual deficits.

57. A medicament for use according to any one of claims 55 or 56, wherein the ischemic stroke is associated with a patient history of traumatic brain injury or sequelae of cerebrovascular disease.

58. The medicament for use according to claim 49, wherein the cerebrovascular disease is selected from the group consisting of: i. Non-traumatic subarachnoid hemorrhage, ii. Non-traumatic intracerebral hemorrhage, iii. Other and unspecified non-traumatic intracranial hemorrhage, iv. Cerebral infarction, v. Occlusion and stenosis of the anterior cerebral artery without causing cerebral infarction, vi. Occlusion and stenosis of cerebral arteries that do not lead to cerebral infarction, vii. Other cerebrovascular diseases, viii. Cerebrovascular disorders associated with other diseases (cerebrovascular disorders classified elsewhere), and ix. Sequelae of cerebrovascular disease.

59. A medicament for use according to claim 49, wherein the disease of the arteries, arterioles or capillaries is selected from the group consisting of: i. Atherosclerosis, ii. Aortic aneurysm and dissection, iii. Other aneurysms, iv. Other peripheral vascular diseases, v. Arterial embolism and thrombosis, vi. Atherosclerotic embolism, vii. Septic arterial embolism, viii. Other diseases of arteries and arterioles, ix. Diseases of the capillaries, and x. A disorder of the arteries, arterioles, or capillaries associated with another disease (a disorder of the arteries, arterioles, or capillaries classified in Diseases elsewhere).

60. The medicament for use according to claim 49, wherein the disease of the arteries, arterioles or capillaries is a chronic arterial occlusive disease, such as atherosclerotic chronic arterial occlusive disease or vascular sclerosis.

61. A medicament for use according to claim 49, wherein the circulatory symptom, sign or clinical finding is a symptom or sign related to the circulatory system, such as an undiagnosed abnormal blood pressure reading, such as cardiac arrest.

62. A medicament for use according to claim 49, wherein the disease of the myocardium or heart chambers is a cardiomyopathy, such as dilated cardiomyopathy.

63. A medicament for use according to claim 48, wherein the disease of the immune system is a non-organ specific systemic autoimmune disorder, such as a vasculitis, such as thromboangiitis obliterans (Buerger's disease).

64. The medicament for use according to claim 48, wherein the disease of the nervous system is selected from the group consisting of: i. Movement disorders, such as Parkinson's syndrome, such as Parkinson's disease, ii. Multiple sclerosis or other white matter disorders, such as multiple sclerosis, and iii. Conditions with neurocognitive impairment as a predominant feature, such as Alzheimer's disease.

65. A medicament for use according to claim 48, wherein the disease of the musculoskeletal system or connective tissue is a condition associated with the spine, such as a herniated disc.

66. A medicament for use according to claim 48, wherein the disease of the circulatory system, the disease of the immune system, the disease of the nervous system, or the disease of the musculoskeletal system or connective tissue is or is associated with diabetes.

67. A medicament for use according to claim 66, wherein the diabetes is selected from type 1 diabetes and type 2 diabetes.

68. A medicament for use according to any one of the preceding claims, wherein the subject suffers from diabetes.

69. A medicament for use according to any one of the preceding claims, wherein the subject is a mammal.

70. A medicament for use according to claim 69, wherein the mammal is a human.

71. A method for treating or preventing a disease or condition in a subject, wherein the disease or condition is selected from the group consisting of: i. Diseases of the circulatory system, ii. Damage caused by external factors, iii. Diseases of the immune system, iv. Diseases of the nervous system, and v. Diseases of the musculoskeletal system or connective tissue, The method comprises administering to a subject in need thereof a therapeutically effective amount of an agent as defined in any one of claims 1 to 47.

72. Use of an agent as defined in any one of claims 1 to 47 for the manufacture of a medicament for the treatment or prevention of a disease or condition selected from the group consisting of: i. Diseases of the circulatory system, ii. Damage caused by external factors, iii. Diseases of the immune system, iv. Diseases of the nervous system, and v. Diseases of the musculoskeletal system or connective tissue.

73. A medicament comprising: a) a peptide selected from the group consisting of: (i) a peptide comprising or consisting of an amino acid sequence of the following general formula: X5X6SX7X8YGLR (SEQ ID NO: 1) in: X5 is D or G; X6 is I or G; X7 is V or L; X8 is V or A; (ii) a peptide comprising or consisting of an amino acid sequence of the following general formula: X 14 LX 15 YGIK(SEQ ID NO:105) in: X 14 is E or G; X 15 is S or T; (iii) a peptide comprising or consisting of an amino acid sequence selected from the group consisting of: VDTYDGDISVVYGL(SEQ ID NO:34), VDTYDGDISVVYG(SEQ ID NO:35), VDTYDGDISVVY (SEQ ID NO: 36), VDTYDGDISVV (SEQ ID NO: 37), VDTYDGDISV (SEQ ID NO: 38), VDTYDGDIS (SEQ ID NO: 39), VDTYDGRGDSVVYGLR(SEQ ID NO:40), VDVPNGDISLAYGL(SEQ ID NO:41), VDVPNGDISLAYG(SEQ ID NO:42), VDVPNGDISLA (SEQ ID NO: 43), VDVPNGDIS (SEQ ID NO: 44), GDPNDGRGDSVVYGLR(SEQ ID NO:45), LDGLVRAYDNISPVG(SEQ ID NO:46), GDPNGDISVVYGLR (SEQ ID NO: 47) VDVPNGDISLAYRLR(SEQ ID NO:48), VDVPEGDISLAYRLR(SEQ ID NO:49), V(beta-D)TYDGDISVVYGLR(SEQ ID NO:50), VDTY(beta-D)GDISVVYGLR(SEQ ID NO:51), VDTYDG(beta-D)ISVVYGLR(SEQ ID NO:52); CLAEIDSC (circular) (SEQ ID NO: 130), CFKPLAEIDSIECSYGIK(cyclic) (SEQ ID NO: 131), cyclic CFKPLAEIDSIEC (SEQ ID NO: 132), KPLAEIDSIELSYGI(SEQ ID NO:133), KPLAEIDSIELSYG(SEQ ID NO:134), KPLAEIDSIELSY(SEQ ID NO:135), KPLAEIDSIELS(SEQ ID NO:136), KPLAEIDSIEL (SEQ ID NO: 137), and KPLAEIDSIE (SEQ ID NO: 138); b) a polynucleotide which, when expressed, encodes the peptide of a); c) a vector comprising the polynucleotide of b); or d) a cell comprising the polynucleotide of b) or the vector of c) It is used to improve post-operative vascularization in a subject.

74. Medicament for use according to claim 73, wherein the surgery is a surgery of the cardiovascular system.

75. A medicament for use according to any one of claims 73 or 74, wherein the surgery on the cardiovascular system is a vascular transplant.

76. A medicament for use according to any one of claims 73 to 75, wherein the subject has undergone a transplant.

77. A medicament for use according to claim 76, wherein the transplant is a transplant of organs, tissues or cells.

78. The medicament for use according to claim 77, wherein the transplantation of said cells is a transplantation of bone marrow cells.

79. A medicament for use according to claim 77, wherein the transplantation of the organ is a transplantation of heart or cardiovascular tissue.

80. A method for inducing angiogenesis, the method comprising administering to a subject an agent as defined in any one of claims 1 to 47.

81. An implant comprising a peptide selected from the group consisting of: (i) a peptide comprising or consisting of an amino acid sequence of the following general formula: X5X6SX7X8YGLR (SEQ ID NO: 1) in: X5 is D or G; X6 is I or G; X7 is V or L; X8 is V or A; (ii) a peptide comprising or consisting of an amino acid sequence of the following general formula: X 14 LX 15 YGIK(SEQ ID NO:105) in: X 14 is E or G; X 15 is S or T; (iii) a peptide comprising or consisting of an amino acid sequence selected from the group consisting of: VDTYDGDISVVYGL(SEQ ID NO:34), VDTYDGDISVVYG(SEQ ID NO:35), VDTYDGDISVVY (SEQ ID NO: 36), VDTYDGDISVV (SEQ ID NO: 37), VDTYDGDISV (SEQ ID NO: 38), VDTYDGDIS (SEQ ID NO: 39), VDTYDGRGDSVVYGLR(SEQ ID NO:40), VDVPNGDISLAYGL(SEQ ID NO:41), VDVPNGDISLAYG(SEQ ID NO:42), VDVPNGDISLA (SEQ ID NO: 43), VDVPNGDIS (SEQ ID NO: 44), GDPNDGRGDSVVYGLR(SEQ ID NO:45), LDGLVRAYDNISPVG(SEQ ID NO:46), GDPNGDISVVYGLR (SEQ ID NO: 47) VDVPNGDISLAYRLR(SEQ ID NO:48), VDVPEGDISLAYRLR(SEQ ID NO:49), V(beta-D)TYDGDISVVYGLR(SEQ ID NO:50), VDTY(beta-D)GDISVVYGLR(SEQ ID NO:51), VDTYDG(beta-D)ISVVYGLR(SEQ ID NO:52); CLAEIDSC (circular) (SEQ ID NO: 130), CFKPLAEIDSIECSYGIK(cyclic) (SEQ ID NO: 131), cyclic CFKPLAEIDSIEC (SEQ ID NO: 132), KPLAEIDSIELSYGI(SEQ ID NO:133), KPLAEIDSIELSYG(SEQ ID NO:134), KPLAEIDSIELSY(SEQ ID NO:135), KPLAEIDSIELS(SEQ ID NO:136), KPLAEIDSIEL (SEQ ID NO: 137), and KPLAEIDSIE (SEQ ID NO: 138).

82. An implant according to claim 81, wherein the implant is coated with a composition comprising an agent according to any one of the preceding claims.

83. An implant according to claim 81, wherein said implant is an implant of biomaterial.

84. An implant according to claim 83, wherein the biomaterial is bone.

85. An implant according to claim 81, wherein said implant is a medical device.

86. An implant according to claim 85, wherein the medical device is a stent.

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