# Biomechanical Signaling in Vascular Smooth Muscle Cell Proliferative Disease Following Functional Loss of Elastin

> **NIH NIH F31** · YALE UNIVERSITY · 2020 · $45,520

## Abstract

PROJECT SUMMARY
Loss of the extracellular matrix (ECM) protein elastin leads to the uncontrolled proliferation of vascular smooth
muscle cells (VSMCs). This proliferation is accompanied by a loss in contractility of VSMCs and in humans
manifests as the condition supravalvular aortic stenosis (SVAS). SVAS patients experience progressive
occlusion of their arterial lumen, ultimately leading to vessel stiffening and heart failure, for which the
mechanisms remain largely unknown. Preliminary data has shown an upregulation of both chondroitin sulfate
and the associated proteoglycan versican in the ascending aortas of elastin haploinsufficient mouse models, and
both have been linked to impaired elastogenesis and hyperproliferation. Further, as signaling by integrin β3 and
FAK is upregulated in SVAS, while expression of smooth muscle contractile markers is reduced, I hypothesize
that abnormal ECM composition under elastin haploinsufficiency is recognized and transduced by the internal
VSMC environment, leading to a shift from a differentiated to a proliferative phenotype. I will assess this
hypothesis using induced pluripotent stem cells (iPSCs) as a model platform, as iPSCs present a limitless supply
of patient-specific cells unattainable through other conventional methods and complement my findings with an
in vivo mouse model of SVAS. In Aim 1, I will phenotypically validate elastin haploinsufficient iPSC-derived
VSMCs specific to the neural crest lineage to phenocopy SVAS and try to rescue the phenotype through
interfering with versican assembly in vivo and in vitro. In Aim 2, I will study the biomechanical signal transduction
involved in the phenotypic switching of elastin haploinsufficient VSMCs from a differentiated, contractile state to
a dedifferentiated, proliferative state in both iPSC and mouse models of SVAS. These aims involve in vivo studies
of murine models, immunofluorescence, western blotting, qPCR, 2D- and 3D-modeling using iPSCs. The
objectives of these aims are to identify key factors in the uncontrolled proliferation observed by VSMCs under
elastin haploinsufficiency, and methods of rescuing this defect. This proposal addresses important, understudied
mechanisms of vascular proliferation, and has the potential to facilitate the development of therapeutics for these
currently incurable diseases.

## Key facts

- **NIH application ID:** 10058762
- **Project number:** 5F31HL143924-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Matthew W Ellis
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058762

## Citation

> US National Institutes of Health, RePORTER application 10058762, Biomechanical Signaling in Vascular Smooth Muscle Cell Proliferative Disease Following Functional Loss of Elastin (5F31HL143924-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10058762. Licensed CC0.

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