BEYOND CONTRACTILITY: PHENOTYPIC SWITCHING OF VASCULAR SMOOTH MUSCLE CELLS IN ATHEROSCLEROSIS.

Atherosclerosis is a complex and dynamic vascular disease driven by chronic inflammation, lipid accumulation, and profound cellular remodeling within the arterial wall. Among the cellular components of the atherosclerotic plaque, vascular smooth muscle cells (VSMCs) play a pivotal and increasingly recognized role. VSMCs display a high degree of phenotypic adaptability, enabling dynamic responses to vascular injury and metabolic stress. Under conditions of vascular injury, oxidative stress, and inflammatory signaling, VSMCs undergo extensive phenotypic modulation characterized by loss of the contractile program and acquisition of synthetic, proliferative, and migratory properties. Recent lineage-tracing studies have further demonstrated that VSMCs can adopt diverse alternative phenotypes, including macrophage-like, foam cell-like, osteogenic, and mesenchymal-like states, thereby actively contributing to plaque growth, calcification, and structural remodeling. This review summarizes current knowledge on the molecular mechanisms governing VSMC phenotypic modulation in atherosclerosis, highlighting key transcriptional regulators and signaling pathways such as PDGF signaling, TGF-β pathways, KLF4, TCF21, and regulatory non-coding RNAs. We also discuss the dual and context-dependent roles of VSMCs in plaque development, emphasizing their contribution to both disease progression and plaque stabilization through extracellular matrix production and fibrous cap formation. Elucidating the mechanisms that control VSMC phenotypic plasticity may provide new opportunities for therapeutic intervention aimed at limiting plaque progression and improving plaque stability in atherosclerotic cardiovascular disease.