# Epigenetic control of smooth muscle cell phenotype during microvascular remodeling

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $364,153

## Abstract

PROJECT SUMMARY
Peripheral Artery Disease (PAD) is an occlusive disease of the lower extremity arteries leading to debilitating
complications (e.g. claudication, amputation) due to defect in proper vascularization and efficient vascular
remodeling. Recent attempts to promote therapeutic angiogenesis by VEGF therapies in patients with PAD have
failed, perhaps because these strategies have only not targeted smooth muscle cells (SMC), cells that are
essential for remodeling of capillaries and terminal arterioles (i.e. arteriogenesis) to increase blood distribution
to ischemic regions. Arteriogenesis relies on the ability of SMC to be plastic and undergo a reversible phenotypic
switching where they transiently downregulate their contractile apparatus, participate in capillary investment, and
then re-differentiate back to the contractile state. However, the understanding of the mechanisms controlling
SMC ability to re-differentiate and the retention of their lineage memory in vivo is limited. We previously identified
an epigenetic signature specific to the SMC lineage consisting of the dimethylation of the lysine 4 of histone 3
(H3K4me2) on the promoters of the SMC marker genes (referred as SMC-H3K4me2) that is retained during
SMC dedifferentiation. These observations suggest that SMC-H3K4me2 could play a pivotal role in maintenance
of SMC identity and retention of lineage memory and could be a key mechanism controlling SMC participation
in arteriogenesis. Studies in this proposal will test the central hypothesis that H3K4me2 controls the SMC
differentiation state and enables SMC involvement in collateral capillary investment and muscularization during
arteriogenesis by promoting the recruitment of TET2 on SMC marker genes. Consistent with this hypothesis, our
preliminary studies, utilizing a novel locus-specific epigenome editing system to remove specifically H3K4me2
on the SMC marker genes, provide evidence that SMC-H3K4me2 tightly regulates SMC differentiation state and
show that H3K4me2 interacts with Ten-eleven translocation (TET2), a key enzyme mediating DNA demethylation
and a master regulator of SMC differentiation. Our central hypothesis will be further tested by addressing the
following specific aims. Aim 1 will determine the impact of loss of SMC-H3K4me2 on SMC participation to
arteriogenesis. The functional consequences of SMC-H3K4me2 removal on SMC phenotype, their ability to
invest capillaries, as well as tissue reperfusion will be evaluated. Aim 2 will test the hypothesis that H3K4me2
plays a key role in promoting SMC differentiation by serving as a docking site for TET2 on the SMC marker
genes. We expect the completion of these studies will lead to the identification of novel mechanisms controlling
smooth muscle cell identity, plasticity, and lineage memory and their participation to beneficial microvascular
arterialization and maturation. These results could serve from the development of new strategies for enhancing
therapeutic vascul...

## Key facts

- **NIH application ID:** 10371189
- **Project number:** 5R01HL146465-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Delphine Gomez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $364,153
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371189

## Citation

> US National Institutes of Health, RePORTER application 10371189, Epigenetic control of smooth muscle cell phenotype during microvascular remodeling (5R01HL146465-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10371189. Licensed CC0.

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