Endothelial Cell Size Regulation for Angiogenesis in Aging

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Solution Overview

Problem

Age-dependent decline in angiogenesis leads to the development of aging-associated diseases, and the direct effects of endothelial cell size on angiogenic processes have not been fully explored.

Innovation Solution

Administering ML141 or its derivatives to stimulate Yes-associated protein (YAP1) nuclear translocation, thereby reducing endothelial cell size and modulating CDC42 activity to restore angiogenesis in aged subjects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Shape

If endothelial cells are cultured on substrates of different stiffness or at different densities, then cell size and shape change, but angiogenic gene expression and EC proliferation are modulated

Engineering Contradiction:

Improvecell size and shapeVSAvoidEC proliferation

Core Design Contradiction:

ShapeVSProductivity

Solution Approach 1:

The patent applies parameter changes by manipulating substrate stiffness and cell density to control endothelial cell size and shape, which in turn modulates angiogenic gene expression and EC proliferation. This resolves the contradiction by showing that physical parameters can be adjusted to achieve desired biological outcomes.

Inventive Principle:

Principle #35Parameter changes

2Shape

If ECM stiffness and blood flow are altered in aged tissues, then cell size and shape change, but angiogenesis is suppressed

Engineering Contradiction:

Improvecell size and shapeVSAvoidangiogenesis

Core Design Contradiction:

ShapeVSReliability

Solution Approach 1:

The patent employs feedback mechanisms where YAP1 nuclear translocation, triggered by cell size changes in response to ECM stiffness and blood flow alterations, provides a regulatory signal that restores angiogenesis in aged tissues. This feedback loop resolves the contradiction by dynamically adjusting biological processes based on physical conditions.

Inventive Principle:

Principle #23Feedback

3Shape

If senescent cells or highly passaged cells are used, then cell size increases, but EC proliferation and angiogenesis are reduced

Engineering Contradiction:

Improvecell sizeVSAvoidEC proliferation

Core Design Contradiction:

ShapeVSProductivity

Solution Approach 1:

The patent inverts the conventional wisdom by showing that reducing cell size (rather than increasing it) restores YAP1 nuclear translocation and enhances EC proliferation and angiogenesis in senescent and highly passaged cells. This inversion resolves the contradiction by reversing the expected relationship between cell size and proliferation.

Inventive Principle:

Principle #13The other way round (Inversion)

4Productivity

If ML141 is administered to stimulate YAP1 nuclear translocation, then endothelial cell size is reduced and angiogenesis is restored, but the mechanism by which cell size directly controls proliferation needs to be explored

Engineering Contradiction:

ImproveangiogenesisVSAvoidmechanism exploration

Core Design Contradiction:

ProductivityVSDifficulty of detecting and measuring

Solution Approach 1:

The patent uses YAP1 as an intermediary molecule that mediates the effect of cell size reduction on EC proliferation and angiogenesis. ML141 stimulates YAP1 nuclear translocation, which then drives the desired biological effects. This intermediary approach resolves the contradiction by providing a measurable molecular mechanism linking cell size to proliferation.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS12433871B2Effects of age-dependent changes in cell size on endothelial cell growth

Publication Date: 2025.10.07 MEDICAL COLLEGE OF WISCONSIN INC

AI summary

Described herein are angiogenic stimulating compositions comprising ML141 or a derivative thereof and methods of use of said angiogenic stimulating compositions for the treatment or prevention of a disease or injury in a subject, preferably a human subject of at least 50 years of age.