The Complex Role of Methylation in Regulating Vascular Smooth Muscle Cell Phenotypic States in Vascular Remodeling and Atherosclerosis

Vascular smooth muscle cell (VSMC) control of phenotypic states through regulation of contractile gene expression is critical for vascular homeostasis and for participation in pathological vascular remodeling, such as atherosclerosis. Cohorts of molecular and cellular processes, including transcriptional and post-transcriptional repression of VSMC contractile genes, context-dependent activation of pathological gene sets, proliferation, and migration, coordinately contribute to SMC phenotypic plasticity. Epigenetic (histone post-translational modifications, DNA methylation) and epitranscriptomic (RNA modifications) mechanisms have been implicated in the activation or repression of the VSMC gene repertoire. Among them, methylation exhibits complex, multifaceted, and, in some instances, opposing roles in regulating gene activation. Methylation-mediated epigenetic programming complexity stems from the multiplicity of methylation substrates and enzymes regulating methylation and demethylation. The role and relevance of methylation in regulating VSMC phenotype are often restricted to a given methylation substrate, methylation enzymes, or subsets of genes. The goal of this review is to integrate in vitro and in vivo studies that uncover methylation-mediated VSMC regulation, to assess the overall contribution of methylation-regulating enzymes. We will explore how atherosclerosis-relevant upstream regulatory mechanisms and rate-limiting cofactors of methylation enzymes, including inflammation, metabolism, and hypoxia, affect methylation enzyme activity. Lastly, we will discuss emerging evidence for non-canonical mechanisms by which methylation enzymes may regulate gene expression and their potential role in regulating VSMC phenotype and function.