ArticleCirculation research2021
FAK Activation Promotes SMC Dedifferentiation via Increased DNA Methylation in Contractile Genes.
Article in Circulation research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 37 citations in OpenAlex.
- The Complex Role of Methylation in Regulating Vascular Smooth Muscle Cell Phenotypic States in Vascular Remodeling and Atherosclerosis.Biomolecules · 2026Review
- Focal adhesion proteins confer smooth muscle anoikis resistance and protection against aortic aneurysm and dissection.JCI insight · 2026Article
- Modulating hypertrophic scar formation by targeting endothelial transient receptor potential vanilloid-1/nuclear factor kappa-B/interleukin-6 axis to regulate angiogenesis.Burns & trauma · 2026Article
- Focal Adhesion Kinase Promotes Calcification of Vascular Smooth Muscle Cells via Regulation of Histone Deacetylase 4 and 5.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- The inner nuclear membrane protein LEMD3 organizes the 3D chromatin architecture to maintain vascular smooth muscle cell identity.Nature communications · 2025Article
- Matrix metalloproteinase-3 promotes arteriovenous fistula failure by regulating FAK-AKT signaling.bioRxiv : the preprint server for biology · 2025Article
- HINT1 aggravates aortic aneurysm by targeting ITGA6/FAK axis in vascular smooth muscle cells.The Journal of clinical investigation · 2025Article
- Characterization of Protein Expression and Signaling Pathway Activation That May Contribute to Differential Biological Functions in Porcine Arterial and Venous Smooth Muscle Cells.International journal of molecular sciences · 2025Article
- Endothelial TRIM35-Regulated MMP10 Release Exacerbates Calcification of Vascular Grafts.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- FAK inhibition disrupts tumor growth, apoptosis, and transcriptional regulation in GI-NETs.Endocrine oncology (Bristol, England) · 2025Article
- Mitochondria-Targeted DNA Repair Glycosylase hOGG1 Protects Against HFD-Induced Liver Oxidative Mitochondrial DNA Damage and Insulin Resistance in OGG1-Deficient Mice.International journal of molecular sciences · 2024Article
- Gene inactivation of lysyl oxidase in smooth muscle cells reduces atherosclerosis burden and plaque calcification in hyperlipidemic mice.Atherosclerosis · 2024Article
- Focal adhesion kinase signaling - tumor vulnerabilities and clinical opportunities.Journal of cell science · 2024Review
- FAK regulates tension transmission to the nucleus and endothelial transcriptome independent of kinase activity.Cell reports · 2024Article
- Methylation in cornea and corneal diseases: a systematic review.Cell death discovery · 2024Review
- The Exacerbating Effects of the Tumor Necrosis Factor in Cardiovascular Stenosis: Intimal Hyperplasia.Cancers · 2024Review
- Chromatin modifiers in human disease: from functional roles to regulatory mechanisms.Molecular biomedicine · 2024Review
- Influence of DNA Methylation on Vascular Smooth Muscle Cell Phenotypic Switching.International journal of molecular sciences · 2024Review
- FAK Family Kinases: A Potential Therapeutic Target for Atherosclerosis.Diabetes, metabolic syndrome and obesity : targets and therapy · 2024Review
- Harnessing the Regenerative Potential of Fetal Mesenchymal Stem Cells and Endothelial Colony-Forming Cells in the Biofabrication of Tissue-Engineered Vascular Grafts (TEVGs).Journal of tissue engineering and regenerative medicine · 2024Article
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 2 countries.
Funding
Abstract
rationaleVascular smooth muscle cells (SMCs) exhibit remarkable plasticity and can undergo dedifferentiation upon pathological stimuli associated with disease and interventions.
objectiveAlthough epigenetic changes are critical in SMC phenotype switching, a fundamental regulator that governs the epigenetic machineries regulating the fate of SMC phenotype has not been elucidated. METHODS AND
resultsUsing SMCs, mouse models, and human atherosclerosis specimens, we found that FAK (focal adhesion kinase) activation elicits SMC dedifferentiation by stabilizing DNMT3A (DNA methyltransferase 3A). FAK in SMCs is activated in the cytoplasm upon serum stimulation in vitro or vessel injury and active FAK prevents DNMT3A from nuclear FAK-mediated degradation. However, pharmacological or genetic FAK catalytic inhibition forced FAK nuclear localization, which reduced DNMT3A protein via enhanced ubiquitination and proteasomal degradation. Reduced DNMT3A protein led to DNA hypomethylation in contractile gene promoters, which increased SMC contractile protein expression. RNA-sequencing identified SMC contractile genes as a foremost upregulated group by FAK inhibition from injured femoral artery samples compared with vehicle group. DNMT3A knockdown in injured arteries reduced DNA methylation and enhanced contractile gene expression supports the notion that nuclear FAK-mediated DNMT3A degradation via E3 ligase TRAF6 (TNF [tumor necrosis factor] receptor-associated factor 6) drives differentiation of SMCs. Furthermore, we observed that SMCs of human atherosclerotic lesions exhibited decreased nuclear FAK, which was associated with increased DNMT3A levels and decreased contractile gene expression.
conclusionsThis study reveals that nuclear FAK induced by FAK catalytic inhibition specifically suppresses DNMT3A expression in injured vessels resulting in maintaining SMC differentiation by promoting the contractile gene expression. Thus, FAK inhibitors may provide a new treatment option to block SMC phenotypic switching during vascular remodeling and atherosclerosis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.