Atherosclerosis is a complex disease involving pathophysiological activation of multiple cell types, such as smooth muscle cells (SMCs), endothelial cells, and immune cells.1 With the development of single-cell genomic technologies, emerging studies of both murine atherosclerotic models and human atherosclerotic plaques have revealed the heterogeneity of cell composition in lesions.2–5 However, the regulation of involved cell types, their dynamics during atherosclerosis, and their relationship with risk of human cardiovascular disease (CVD) remain unclear.

SMCs are proposed to play central roles in plaque development, progression, and stability through “phenotypic switching,” a process of medial SMC proliferation, dedifferentiation, and migration into the intimal lesions in response to atherogenic stimuli.6,7 Recent SMC-lineage tracing studies in mouse models provided evidence that SMC-derived cells contributed a large proportion of cells within lesions.8,9 Human genetic studies have also refocused attention on genes that regulate SMC functions as directly causal in coronary artery disease (CAD).10 Yet most current treatments for atherosclerosis target low-density lipoprotein cholesterol and have little direct impact on SMCs per se.

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