Abstract
Atherosclerosis (AS) is a complex pathology process involving intricate interactions among various cells and biological processes. Vascular smooth muscle cells (VSMCs) are the predominant cell type in normal arteries, and under atherosclerotic stimuli, VSMCs respond to altered blood flow and microenvironment changes by downregulating contractile markers and switching their phenotype. This review overviews the diverse phenotypes of VSMCs, including the canonical contractile VSMCs, synthetic VSMCs, and phenotypes resembling macrophages, foam cells, myofibroblasts, osteoblasts/chondrocytes, and mesenchymal stem cells. We summarize their presumed protective and pro-atherosclerotic roles in AS development. Additionally, we underscore the molecular mechanisms and regulatory pathways governing VSMC phenotypic switching, encompassing transcriptional regulation, biochemical factors, plaque microenvironment, epigenetics, miRNAs, and the cytoskeleton, emphasizing their significance in AS development. Finally, we outline probable future research directions targeting VSMCs, offering insights into potential therapeutic strategies for AS management.