Vascular smooth muscle cells in atherosclerosis

Abstract

Vascular smooth muscle cells (VSMCs) are a major cell type present at all stages of an atherosclerotic plaque. According to the ‘response to injury’ and ‘vulnerable plaque’ hypotheses, contractile VSMCs recruited from the media undergo phenotypic conversion to proliferative synthetic cells that generate extracellular matrix to form the fibrous cap and hence stabilize plaques. However, lineage-tracing studies have highlighted flaws in the interpretation of former studies, revealing that these studies had underestimated both the content and functions of VSMCs in plaques and have thus challenged our view on the role of VSMCs in atherosclerosis. VSMCs are more plastic than previously recognized and can adopt alternative phenotypes, including phenotypes resembling foam cells, macrophages, mesenchymal stem cells and osteochondrogenic cells, which could contribute both positively and negatively to disease progression. In this Review, we present the evidence for VSMC plasticity and summarize the roles of VSMCs and VSMC-derived cells in atherosclerotic plaque development and progression. Correct attribution and spatiotemporal resolution of clinically beneficial and detrimental processes will underpin the success of any therapeutic intervention aimed at VSMCs and their derivatives.

Key points

  • Vascular smooth muscle cells (VSMCs) and VSMC-derived cells are a major source of plaque cells and extracellular matrix at all stages of atherosclerosis.

  • VSMCs contribute to many different plaque cell phenotypes, including extracellular-matrix-producing cells of the fibrous cap, macrophage-like cells, foam cells, mesenchymal stem-cell-like cells and osteochondrogenic cells.

  • Progress has been made in identifying the source of VSMCs and VSMC-derived cells in atherosclerotic plaques, highlighting the importance of the developmental origin, clonal expansion and phenotype switching of VSMCs in atherosclerosis.

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Fig. 1: Overview of the role of VSMCs in atherosclerosis.
Fig. 2: VSMCs in early atherosclerosis.
Fig. 3: VSMCs in late atherosclerosis.
Fig. 4: VSMCs in clinical sequelae of atherosclerosis.

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G.L.B., H.F.J. and M.C.H.C. wrote the manuscript. H.F.J. and M.C.H.C. contributed equally. All the authors researched data for the article, discussed its content, reviewed the manuscript for important intellectual content and edited the manuscript before submission.

Correspondence to Ziad Mallat.

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Nature Reviews Cardiology thanks D. M. Greif, P. Libby, M. W. Majesky and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Lineage tracing

Technique that enables the fate of labelled cells to be traced in vivo to allow the identification of progeny cells.

Mesenchymal stem cell

Multipotent stromal cell.

Phenotype switching

Process by which vascular smooth muscle cells (VSMCs) alter their phenotype, often inferred through decreased expression of VSMC-specific genes encoding contractile proteins and/or increased expression of markers typical of synthetic VSMCs or other cell types.

Foam cells

Lipid-laden cells with a foamy appearance.

Osteochondrogenic cells

Cells capable of generating osteocytes and/or chondrocytes.

Clonal expansion

Proliferation of a single or limited number of ancestral cells.

Shelterin complex

Multiprotein complex (including telomeric repeat-binding factor 2 (TRF2)) that binds to the repetitive sequences of telomeric DNA, protecting against DNA damage.

Response to retention hypothesis

Hypothesis that subendothelial retention of lipid, in the form of lipoproteins, is the initial step in atherogenesis.

Vulnerable plaque

Atherosclerotic plaque with a phenotype associated with increased risk of rupture, also known as thin-cap fibroatheromas, defined by a thin fibrous cap (<65 μm) and a large necrotic core.

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Basatemur, G.L., Jørgensen, H.F., Clarke, M.C.H. et al. Vascular smooth muscle cells in atherosclerosis. Nat Rev Cardiol 16, 727–744 (2019). https://doi.org/10.1038/s41569-019-0227-9

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