Phenotype

Pathology

Transcriptome

Receptor

Mesenchymal stem cell

Macrophage

Fibrosis

Smooth muscle

Biology

Gene

Mural cell

Endocrinology

Endothelial stem cell

Gene expression

Extracellular matrix

In vitro

Myofibroblast

Foam cell

Fibrous cap

Vascular smooth muscle

Pericyte

Phenotypic switching

Cell biology

Biochemistry

Medicine

Paracrine signalling

Cardiovascular Research

Vascular smooth muscle cells (VSMCs) are key participants in both early and late-stage atherosclerosis. VSMCs invade the early atherosclerotic lesion from the media, expanding lesions, but also forming a protective fibrous cap rich in extracellular matrix to cover the 'necrotic' core. Hence, VSMCs have been viewed as plaque-stabilizing, and decreased VSMC plaque content-often measured by expression of contractile markers-associated with increased plaque vulnerability. However, the emergence of lineage-tracing and transcriptomic studies has demonstrated that VSMCs comprise a much larger proportion of atherosclerotic plaques than originally thought, demonstrate multiple different phenotypes in vivo, and have roles that might be detrimental. VSMCs down-regulate contractile markers during atherosclerosis whilst adopting alternative phenotypes, including macrophage-like, foam cell-like, osteochondrogenic-like, myofibroblast-like, and mesenchymal stem cell-like. VSMC phenotypic switching can be studied in tissue culture, but also now in the media, fibrous cap and deep-core region, and markedly affects plaque formation and markers of stability. In this review, we describe the different VSMC plaque phenotypes and their presumed cellular and paracrine functions, the regulatory mechanisms that control VSMC plasticity, and their impact on atherogenesis and plaque stability.

Vascular smooth muscle cells in atherosclerosis: time for a re-assessment