# Endothelial-to-mesenchymal transition and atherosclerosis

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $835,601

## Abstract

Project Summary/Abstract
This competitive renewal is based on work demonstrating that a subpopulation of endothelial cells (ECs) in
atherosclerotic plaques undergo a transition to a mesenchymal cell fate that involves loss of barrier function,
expression of inflammatory genes and remodeling of the extracellular matrix. This transition is initiated by
inflammatory signaling that sensitizes cells to TGFβ, which then drives the mesenchymal fate transition. A key
consequence of the mesenchymal phenotype is production of a fibronectin-rich extracellular matrix that amplifies
inflammatory signaling, recruiting leukocytes and production of cytokines. This sequence of events thus creates
positive feedback, a key feature of disease progression and resistance to therapy. Our work during the past grant
cycle has provided evidence that fate switching is driven by a minor subset of pre-existing, susceptible ECs that
drive vessel wall remodeling. Our work has also elucidated novel pathways by which matrix remodeling alters
integrin signaling to enhance inflammatory pathways and promotes disease progression. The overall goal of the
current application is to understand the EC subpopulations and factors that drive fate switching, and the positive
feedback mechanisms that drive disease. Aim 1 will elucidate endothelial heterogeneity in mice and in patients
with atherosclerosis. Aim 2 will characterize disease-prone subset of normal endothelial cells. Aim 3 will
elucidate the role of pro-inflammatory integrin signaling in evolution of EC populations in the atherosclerotic
plaque and the downstream pathways that mediate plaque progression.

## Key facts

- **NIH application ID:** 9973898
- **Project number:** 2R01HL135582-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Martin A Schwartz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $835,601
- **Award type:** 2
- **Project period:** 2017-01-12 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973898

## Citation

> US National Institutes of Health, RePORTER application 9973898, Endothelial-to-mesenchymal transition and atherosclerosis (2R01HL135582-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9973898. Licensed CC0.

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