Epigenetic regulation of vascular smooth muscle cell phenotypes in atherosclerosis

Vascular smooth muscle cells (VSMCs) in adult arteries maintain substantial phenotypic plasticity, which allows for the reversible cell state changes that enable vascular remodelling and homeostasis. In atherosclerosis, VSMCs dedifferentiate in response to lipid accumulation and inflammation, resulting in loss of their characteristic contractile state. Recent studies showed that individual, pre-existing VSMCs expand clonally and can acquire many different phenotypes in atherosclerotic lesions. The changes in gene expression underlying this phenotypic diversity are mediated by epigenetic modifications which affect transcription factor access and thereby gene expression dynamics. Additionally, epigenetic mechanisms can maintain cellular memory, potentially facilitating reversion to the contractile state. While technological advances have provided some insight, a comprehensive understanding of how VSMC phenotypes are governed in disease remains elusive. Here we review current literature in light of novel insight from studies at single-cell resolution. We also discuss how lessons from epigenetic studies of cellular regulation in other fields could help in translating the potential of targeting VSMC phenotype conversion into novel therapies in cardiovascular disease.