GRK2 Orchestrates VSMC Phenotypic Modulation via DNMT1-Mediated DNA Methylation Reprogramming

Abstract

Background: Vascular smooth muscle cell (VSMC) phenotypic modulation is responsible for the pathogenesis of hyper-muscularized arterial diseases. Recent studies have highlighted the critical role of epigenetic regulation in VSMC fate. However, the mechanisms underlying the precise regulation of the epigenetic machinery in VSMC remain unclear.

Methods: Using mouse aortic smooth muscle cells, carotid artery injury mouse model, and human atherosclerosis data sets, we identified GRK2 (G-protein-coupled receptor kinase 2) as a novel epigenetic regulator governing VSMC fate.

Results: GRK2 expression was found to be elevated in dedifferentiated VSMCs. Pharmacological or genetic silencing of GRK2 inhibited VSMC phenotypic switching. Mechanistic investigations demonstrated that GRK2 modulated VSMC phenotype via DNMT1 (DNA methyltransferase 1)-mediated DNA methylation. GRK2 phosphorylated DNMT1, stabilizing it by modulating its ubiquitination. Hypermethylated VSMC exhibited reduced expression of contractile-associated proteins. Inhibition of DNMT1 abolished the effects of GRK2 overexpression on VSMC phenotype, indicating a DNMT1-mediated mechanism.

Conclusions: Our findings revealed that the GRK2-DNMT1 signaling axis is a critical regulator in VSMC phenotypic switching and present a potential therapeutic target for vascular remodeling.

Keywords: GRKs; cytokines; hyperplasia; methyltransferase; phenotype.