# Endothelial plasticity in cardiac repair after myocardial infarction

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $600,842

## Abstract

Project Summary
Ischemic heart disease is the most common cause of death in the western world, largely due to myocardial
infarction (MI), the irreversible damage of myocardial tissue induced by the blockage in coronary
arteries. After MI, formation of new blood vessels, i.e., neovascularization, is crucial for ischemic tissue
reperfusion and repair. However, the newly formed vasculatures in infarcted tissue are characterized by
functional and structural abnormalities, which compromise vessel delivery function and cardiac repair after
MI. Likewise, aberrant non-productive neovascularization represents a promising therapeutic target for MI
treatment. Here, by utilizing endothelial lineage tracing and single-cell RNAseq technology, our preliminary
studies with a murine MI model reveal robust endothelial cell (EC) plasticity mediated through endothelial
mesenchymal transformation (Endo-MT, i.e., partial endothelial mesenchymal transition) during cardiac
repair after MI. We show that ECs acquire mesenchymal phenotypes including high proliferation and motility
after MI, leading to vascular abnormalities and non-productive neovascularization. We identify a PDGF/NF-
kB/HIF-1a/Snail-mediated axis that controls Endo-MT. Notably, EC-specific deletion of PDGF receptor-b
promotes post-MI tissue repair and cardiac function recovery in mice. Finally, pharmacological inhibition of
PDGF improves cardiac function recovery after MI. In addition, Snail is expressed in human MI-associated
ECs. Based on these findings, we hypothesize that endothelial plasticity drives non-productive
neovascularization and impedes cardiac repair after MI. To test this hypothesis, we will pursue the
following aims: 1) To define the molecular mechanisms for endothelial plasticity after MI; 2) To determine
the in vivo role of endothelial plasticity for aberrant neovascularization and cardiac repair after MI; and 3) To
test experiment therapy that targets PDGFR-mediated endothelial plasticity for MI treatment. Thus, targeting
EC plasticity may offer a promising therapeutic opportunity to recondition vascular microenvironment and
improve cardiac repair and function recovery after MI. Successful completion of this project will provide new
insights into the mechanism for aberrant neovascularization and may lead to development of new
therapeutic revenue for treating ischemic heart disease.

## Key facts

- **NIH application ID:** 10467987
- **Project number:** 5R01HL155198-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Yi Fan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $600,842
- **Award type:** 5
- **Project period:** 2021-08-11 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467987

## Citation

> US National Institutes of Health, RePORTER application 10467987, Endothelial plasticity in cardiac repair after myocardial infarction (5R01HL155198-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10467987. Licensed CC0.

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