# Nuclear FAK-mediated VSMC differentiation via epigenetic reprograming invascular diseases

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $475,418

## Abstract

Project Summary
Vascular smooth muscle cells (VSMCs) can dedifferentiate into a highly proliferative state with less contractile
gene expression upon vessel injury or transdifferentiate into macrophage-like cells (MLCs) during
atherosclerosis progression. These types of phenotypic switching are driven by multiple transcriptional and
epigenetic changes. Despite vicious effects of VSMC dedifferentiation and transdifferentiation in vascular
diseases, direct interventional studies that target vicious VSMC phenotype switching have been lacking. During
VSMC dedifferentiation, increased secretion of matrix and growth factors alter integrin signaling and lead to
aberrant focal adhesion kinase (FAK) activation, which promotes VSMC proliferation. We demonstrated that
FAK is inactive and primarily localized within the nuclei of VSMCs of healthy arteries. However, vessel injury
promoted FAK activation and cytoplasmic relocalization which increased cell cycling. While we also observed
that FAK activation suppresses expression of VSMC contractile genes, the underlying mechanism by which
FAK regulates VSMC contractile genes is not known. Our preliminary data demonstrated that inhibition of FAK
catalytic activity in VSMCs induced nuclear localization of FAK and increased contractile gene transcription.
Through biochemical and proteomics studies, we identified two independent epigenetic repression
machineries, DNA methyltransferase 3A (DNMT3A) and the nucleosome remodeling and deacetylase (NuRD)
complex, as nuclear FAK-interacting partners. Importantly, we found that FAK inhibition decreased DNMT3A
and NuRD component expression, which was associated with decreased DNA methylation and increased
active histone marks (H3K27ac and H4ac) in the contractile gene promoters. Using genetic FAK cytoplasmic
(Cyto) restricted VSMCs, we found that FAK nuclear localization is required for reduction of DNMT3A and
NuRD complex. Furthermore, FAK inhibition blocked advanced atherosclerotic lesion formation in ApoE-/- mice
with decreased DNMT3A and NuRD component expression. This was associated with a thicker smooth muscle
actin positive area, suggesting that FAK inhibition increased VSMC differentiation and plaque stability
compared to control. Our results implicated that FAK activation upon injury or hyperlipidemia stimulation may
contribute to VSMC phenotype switching potentially via epigenetic regulation. Our hypothesis is that FAK
catalytic inhibition forces FAK nuclear localization and promotes VSMC differentiation via reduced expression
of DNMT3A and NuRD. In Aim 1, we will elucidate the molecular mechanism of nuclear FAK-mediated VSMC
phenotypic switching via epigenetic modulation of DNA methylation, and histone modification. In Aim 2, we will
investigate the role of DNMT3A and the NuRD complex in VSMC dedifferentiation upon vascular injury. In Aim
3, we will evaluate the effect of FAK inhibition on blocking VSMC transdifferentiation and promoting plaque
stability in early ...

## Key facts

- **NIH application ID:** 10618482
- **Project number:** 7R01HL158800-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Steve Lim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $475,418
- **Award type:** 7
- **Project period:** 2022-05-16 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10618482

## Citation

> US National Institutes of Health, RePORTER application 10618482, Nuclear FAK-mediated VSMC differentiation via epigenetic reprograming invascular diseases (7R01HL158800-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10618482. Licensed CC0.

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