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

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $465,910

## Abstract

VSMCs dedifferentiate into a proliferative state upon vessel injury or transdifferentiate into macrophage-like
cells (MLCs) during atherosclerosis progression. VSMC phenotypic switching are driven by multiple
transcriptional and epigenetic changes that lead to increased proliferation with reduced contractile gene
expression and increased matrix production, which is detrimental to atherosclerotic lesions, direct
interventional studies that target this process have been lacking. Increased matrix and growth factors alter
integrin signaling and leads to aberrant focal adhesion kinase (FAK) activation, which may promote VSMC
phenotypic switching. We demonstrated that FAK is inactive and primarily localized in the nuclei of VSMCs of
healthy arteries. However, vessel injury promoted FAK activation and cytoplasmic relocalization, which
increased cyclin D1 transcription and cell cycling. While we found that inhibition of FAK activity in VSMCs
induced nuclear localization of FAK and increased contractile gene transcription, the underlying mechanism by
which FAK regulates the contractile genes is not known. We have identified DNA methyltransferase 3A
(DNMT3A) and the nucleosome remodeling and deacetylase (NuRD) complex, two key epigenetic repression
machineries, as nuclear FAK-interacting partners in VSMCs. FAK inhibition decreased DNMT3A and NuRD
component expression, which was associated with decreased DNA methylation and increased active histone
marks within contractile gene promoters. Using genetic FAK cytoplasmic (Cyto) restricted VSMCs, we found
that nuclear FAK is required for reducing DNMT3A/NuRD and for increasing contractile gene expression.
Additionally, ApoE-/-;FAK-Cyto mice showed increased atherosclerosis compared to WT mice, suggesting that
active cytoplasmic FAK exacerbates atherosclerosis. Further, FAK showed increased cytoplasmic localization
and activity within human atherosclerotic lesions compared to healthy specimens. Importantly, FAK inhibitor
reduced advanced atherosclerotic lesions in ApoE-/- mice, which was associated with reduced DNMT3A and
NuRD component expression with increased ACTA2+ cells in the fibrous cap. Our hypothesis is that FAK
catalytic inhibition forces FAK nuclear localization and promotes VSMC differentiation via reduced expression
of epigenetic regulators DNMT3A and NuRD complex. Aim 1 will elucidate the molecular mechanism of
nuclear FAK-mediated VSMC phenotypic switching via epigenetic modulation of DNA methylation, chromatin
remodeling, and histone modification. Aim 2 will investigate the role of DNMT3A and the NuRD complex in
VSMC dedifferentiation upon vascular injury using both DNMT3A and NuRD genetic models. Aim 3 will
evaluate the effect of FAK inhibition on blocking VSMC transdifferentiation and promoting plaque stability in
early and advanced atherosclerosis. This study will provide new insights into VSMC phenotype switching via
FAK-mediated epigenetic control through DNMT3A and NuRD complex stability. T...

## Key facts

- **NIH application ID:** 10825529
- **Project number:** 5R01HL158800-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Steve Lim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $465,910
- **Award type:** 5
- **Project period:** 2022-05-16 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825529

## Citation

> US National Institutes of Health, RePORTER application 10825529, Nuclear FAK-mediated VSMC differentiation via epigenetic reprograming invascular diseases (5R01HL158800-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10825529. Licensed CC0.

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