Vascular smooth muscle cells (vSMCs) play a central role in atherosclerotic plaque development and stability through their remarkable phenotypic plasticity. In healthy vessels, contractile vSMCs maintain vascular tone and structural integrity. During atherogenesis, lipid accumulation, inflammatory cues, growth factors, and mechanical stress drive vSMC dedifferentiation, proliferation, and migration into the intima. This transition involves downregulation of contractile genes regulated by SRF-myocardin and induction of synthetic, proliferative, inflammatory, macrophage-like, or osteogenic phenotypes, mediated in part by KLF4, PDGF, TNFα, oxidized lipids, and TGFβ signaling. Mechanotransduction through integrins and ECM remodeling reinforces these phenotypic shifts, with pathological stretch, matrix stiffening, and provisional matrix deposition promoting plasticity via RhoA/ROCK, FAK, and YAP/TAZ pathways. Clonal expansion of select medial vSMCs further shapes plaque architecture, while non-coding RNAs fine-tune phenotypic modulation at the post-transcriptional level. Collectively, these processes contribute to fibrous cap thinning, impaired efferocytosis, necrotic core expansion, and vascular calcification - features of vulnerable plaques. Here, we review the molecular, mechanical, and post-transcriptional mechanisms driving vSMC phenotypic modulation in atherosclerosis, highlighting their contributions to plaque progression and instability, and discussing emerging areas that may inform future therapeutic strategies.
Frausto et al. (2025) studied this question.