Fate and State of Vascular Smooth Muscle Cells in Atherosclerosis

Abstract

Vascular smooth muscle cells (VSMCs) have long been associated with phenotypic modulation/plasticity or dedifferentiation. Innovative technologies in cell lineage tracing, single-cell RNA sequencing, and human genomics have been integrated to gain unprecedented insights into the molecular reprogramming of VSMCs to other cell phenotypes in experimental and clinical atherosclerosis. The current thinking is that an apparently small subset of contractile VSMCs undergoes a fate switch to transitional, multipotential cells that can adopt plaque-destabilizing (inflammation, ossification) or plaque-stabilizing (collagen matrix deposition) cell states. Several candidate mediators of such VSMC fate and state changes are coming to light with intriguing implications for understanding coronary artery disease risk and the development of new treatment modalities. Here, we briefly summarize some technical and conceptual advancements derived from 2 publications in Circulation and another in Nature Medicine that, collectively, illuminate new research directions to further explore the role of VSMCs in atherosclerotic disease.

Keywords: atherosclerosis; cell differentiation; genetics; genomics; myocytes, smooth muscle.

Figure.

Diverse VSMC-derived cell states in atherosclerosis. The LGALS3+ transitional cell of the intima is derived from dedifferentiated VSMC, perhaps in a deterministic manner. These cells represent pioneer cells of Alencar et al or Stem/Endothelial/Macrophage (SEM) cells of Pan et al and likely are precursors to plaque-stabilizing fibromyocytes of Wirka et al. Depending on micro-environmental signaling cues (e.g., retinoid signaling) and expression level of key transcription factors (e.g., KLF4), transitional cells may differentiate into a number of cells types that lead to fibrous cap formation (e.g., ACTA2+/PHACTR1+ cells) and plaque stability or expansion of the athero-core (osteogenic and inflammatory cells) leading to plaque instability (red zone). Unresolved questions are indicated. See text for more details.