# Atheroprotection by smooth muscle selective RhoGAPs

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $750,361

## Abstract

1. Summary
 Atherosclerosis is a leading cause of morbidity and mortality world-wide. It is clear that vascular smooth
muscle cells (SMCs) play a critical role in plaque progression and stability, but many questions remain in
regard to the source, fate, and function of the phenotypically modulated SMCs within the protective fibrous cap
and necrotic core. Defects in SMC function that lead to hypertension (HTN) and increased vascular stiffness
also affect plaque formation and progression by altering mechanical signaling within the vessel wall. Although
these physiologic parameters are major independent cardiovascular risk factors, we know surprisingly little
about their development, their inter-relationship, or the mechanisms by which they promote atherosclerosis.
We have previously shown that the SMC-selective Rho-specific GAP, GRAF3, reduces blood pressure in mice
and humans by limiting RhoA-dependent SMC contractility in resistance arterioles and went on to identify
rs604723 as the causal variant within the BP-associated locus in this gene. Our more recent data indicate that
GRAF signaling is atheroprotective and inhibits the expression of the contractile and extracellular matrix genes
that drive vascular stiffness, and the pro-inflammatory and pro-calcification gene programs that contribute to
atherosclerotic plaque development and rupture. The overall goals of this proposal are to assess the role of
GRAF3 genotype on cardiovascular outcomes in a large and diverse cardiovascular disease patient
population, to directly measure the contribution of GRAF signaling to atherosclerosis and vascular stiffening,
and to use our understanding of GRAF intra-molecular interactions to identify GRAF-activating compounds that
could be useful for treating HTN and atherosclerotic disease.

## Key facts

- **NIH application ID:** 10540001
- **Project number:** 1R01HL165786-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Christopher P. Mack
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $750,361
- **Award type:** 1
- **Project period:** 2022-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10540001

## Citation

> US National Institutes of Health, RePORTER application 10540001, Atheroprotection by smooth muscle selective RhoGAPs (1R01HL165786-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10540001. Licensed CC0.

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