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Atherosclerosis

Vascular smooth muscle cell plasticity in atherosclerosis

Nature Reviews Cardiology volume 23, page 386 (2026) Cite this article

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Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Atherosclerosis is driven by lipoprotein-driven inflammation in the arterial wall, but the central mechanism underlying lesion progression is the maladaptive response of local vascular wall cells. Early evidence dating back to the pioneering work of Earl Benditt in the early 1970s suggests that vascular smooth muscle cells (VSMCs) might have a central and dynamic role in the development of atherosclerosis. He proposed that atherosclerotic lesions arise through aberrant clonal expansion of arterial wall cells triggered by vascular injury — an idea that challenged the prevailing view of atherosclerosis as a passive lipid-storage disease. Without tools to trace individual cell lineages in vivo, however, the extent and nature of the contributions of VSMCs to plaque formation remained unresolved for decades.

For many years, progress was hindered by reliance on immunostaining for classical VSMC markers such as α-smooth muscle actin (ACTA2, also known as αSMA) and transgelin (also known as SM22α, and encoded by TAGLN), which are rapidly downregulated as VSMCs adapt to inflammatory and lipid-rich environments. As a result, most VSMC subsets within plaques went undetected, reinforcing the long-held misconception that VSMCs contribute to atherosclerosis primarily as a uniform, stabilizing cell population.

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References

Original article

  • Feil, S. et al. Transdifferentiation of vascular smooth muscle cells to macrophage-like cells during atherogenesis. Circ. Res. 115, 662–667 (2014)

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Acknowledgements

L.A.-H. is supported by grants from the Novo Nordisk Foundation (NNF23SA0088590 and NNF25OC0096998).

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Authors and Affiliations

  1. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

    Laura Alonso-Herranz

  2. Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark

    Laura Alonso-Herranz

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  1. Laura Alonso-Herranz
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Correspondence to Laura Alonso-Herranz.

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The author declares no competing interests.

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Cite this article

Alonso-Herranz, L. Vascular smooth muscle cell plasticity in atherosclerosis. Nat Rev Cardiol 23, 386 (2026). https://doi.org/10.1038/s41569-026-01283-x

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