# Mechanisms of epicardium-directed coronary vessel patterning

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2024 · $530,006

## Abstract

The coronary blood vasculature provides the heart with oxygen and nutrients, and removes
metabolic waste. Organization of this contiguous network requires the maturation of vascular
endothelial cells (EC) into arterial and venous fates based upon their location in the heart. While
many of the guidance factors that control vascular patterning have been defined, it is not clear
how spatial information controls cell behavior and identity. The epicardium is a single layer of
mesothelial cells on the surface of the heart that harbors an important population of cardiovascular
progenitors. We previously reported that epicardial epithelial-to-mesenchymal transition (EMT) is
required for coronary EC maturation. New preliminary data reveals profound EC patterning and
specification defects upon disruption of the epicardium, culminating with the inappropriate
localization of angiogenic ECs in the sub-epicardium. To define the cellular and molecular
mechanisms linking epicardial EMT to EC patterning and maturation we performed single cell (sc)
RNA-sequencing of epicardium-derived cells and ECs isolated from the embryonic mouse heart
at key developmental timepoints. This study defined epicardium-derived “shepherding” and
“guidepost” cells that express unique angiogenic chemokine signatures. We provide in vitro and
in vivo evidence that suggest a common mechanism controls EMT and the expression of genes
that encode important guidance cues. We also find that EC localization and arteriovenous fate
specification may be controlled by a common molecular mechanism. Based on previously
published and preliminary data, we hypothesize that EMT controls the expression and
localization of epicardium-derived chemokines that coordinate coronary EC patterning
and AV fate specification in the fetal heart. The current study will interrogate this novel
paradigm of epicardium-directed coronary EC patterning (localization and branching) and
maturation (arteriovenous specification). Here, we will use genetically modified mice, time-lapse
live embryo multi-photon imaging, scRNA-seq and spatial transcriptomics, and cell and molecular
biology approaches to: 1) Define a common mechanism regulating EMT and the expression of
genes that encode EC guidance cues; and 2) Interrogate the mechanisms coordinating
epicardium-directed EC patterning and AV fate specification. We expect these studies will provide
important insights into the mechanisms that control vascular patterning. This study may also
advance our understanding of the developmental origins of coronary artery disease, and lead to
therapeutic strategies that stimulate revascularization and repair of ischemic heart tissue.

## Key facts

- **NIH application ID:** 10908469
- **Project number:** 5R01HL160758-03
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Eric M Small
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $530,006
- **Award type:** 5
- **Project period:** 2022-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908469

## Citation

> US National Institutes of Health, RePORTER application 10908469, Mechanisms of epicardium-directed coronary vessel patterning (5R01HL160758-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10908469. Licensed CC0.

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