Methods for suppressing neovascularization using EphrinB2
A lumen, endothelial cell technology, applied in the field of angiogenesis and neovascularization, can solve problems such as unclear role
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Embodiment 1
[0111] Evrin B2 inhibits growth factor-stimulated EC proliferation and migration
[0112] Treatment of human aortic epithelial cells (HAoEC) with VEGF, bFGF or PDGF-BB (10 ng / mL each) resulted in a 3-10 fold increase in DNA synthesis compared to untreated controls. Ephin B2 inhibited DNA synthesis stimulated by all these stimuli, whereas neither EphB4 nor Ephin B2+EphB4 inhibited. As shown in Figure 1A, the increase in DNA synthesis induced by 10 ng / mL VEGF, bFGF or PDGF-BB was inhibited by 40%, 30% and 90% by 200 μg / mL Evrin B2, respectively. Almost identical results were obtained using human umbilical vein endothelial cells (HUVEC) (Fig. 1B). No apparent apoptotic cells were observed during this incubation period (data not shown). At day 7, VEGF-induced lumen formation was reduced in the Evrin B2-treated group compared to the control group (Fig. 1C). In contrast, VEGF-induced lumen formation was not affected by EphB4 treatment.
[0113] Thus, evotin B2 is capable of inhi...
Embodiment 2
[0116] Effects of Evrin B2 on Growth Factor-Induced Phosphorylation of p42 / 44 ERK and Receptor Autophosphorylation
[0117] To investigate the mechanism by which evotin B2 inhibits VEGF- or bFGF-induced mitogenic responses on HAoECs, we examined the effect of evotin B2 on VEGF- or bFGF-stimulated ERK (p42 / 44) phosphorylation by Western analysis. Stimulation with 10 ng / mL VEGF or bFGF enhanced ERK phosphorylation. Evin B2 inhibits VEGF- and bFGF-induced ERK phosphorylation. For example, 200 μg / mL Evin B2 inhibited VEGF-induced ERK phosphorylation by 70% (Fig. 2A). We then investigated the autophosphorylation of VEGF-receptor 2 (KDR) in VEGF-stimulated HUVECs. 10 ng / mL VEGF increased VEGF-receptor 2 autophosphorylation by 14-fold. Evin B2 did not inhibit autophosphorylation of VEGF-receptor 2 (Fig. 2B). Essentially the same results were obtained with HUVECs (data not shown).
[0118] These results therefore indicate that evotin B2 inhibits VEGF- or bFGF-induced ERK phosphor...
Embodiment 3
[0120] Co-administration of Evrin B2 in mouse cornea inhibits bFGF-induced angiogenesis
[0121] bFGF is known to be a potent angiogenic factor. Since evotin B2 is able to inhibit bFGF-induced proliferation of EC cells, we examined whether evotin B2 is also capable of inhibiting angiogenesis.
[0122] We implanted Hydron pellets that had been infused with human bFGF into the corneas of mice. Six days after implantation, we examined the growth of new blood vessels. bFGF significantly induced angiogenesis in the mouse cornea. We further examined the effects of Ephrin B2 and EphB4 on bFGF-induced corneal neovascularization. Administration of ephrin B2 significantly blocked bFGF-induced angiogenesis, but administration of EphB4 showed no effect. Quantitative analysis also demonstrated that Evrin B2 completely inhibited bFGF-induced corneal neovascularization ( FIG. 3 ).
[0123] Thus, evotin B2 can be used to inhibit angiogenesis and neovascularization. In particular, these ...
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