Smooth Muscle Cell Plasticity as a Central Determinant of Plaque Stability

This review examines how smooth muscle cell (SMC) fate transitions contribute to the central paradox of atherosclerosis: why thin-cap plaques that only mildly narrow the lumen cause most acute events, whereas many severely stenotic lesions remain stable. We propose that interactions between SMC developmental programming and local microenvironments determine whether SMCs build collagen-rich fibrous caps, undergo medial degeneration, or adopt phenotypes that weaken the vessel wall. SMCs show marked plasticity, adopting phenotypes that either strengthen or weaken fibrous caps. Three axes appear central. First, developmental origin imprints durable differences in how coronary, ascending aortic, and abdominal SMCs respond to the same insults. Second, microenvironmental factors such as flow, vessel architecture, aging, and perivascular fat translate identical systemic risks into bed-specific disease patterns. Third, the “TGF-β paradox” reflects context-dependent signaling in which dose, cellular audience, matrix, and timing determine whether TGF-β supports cap formation or drives inflammatory and matrix-degrading programs. Mouse lineage-tracing and human pathology converge on the view that clinical risk correlates more robustly with plaque composition and cap integrity than with stenosis severity. SMC plasticity helps explain why the same systemic risk factors produce different patterns of atherosclerosis in different vascular beds. Developmental imprinting and local cues shape whether SMCs maintain the media and build thick, collagenous caps or instead contribute to cap thinning, core expansion, and aneurysm formation. These insights argue that therapy should move beyond lumen stenosis and focus on preserving or restoring cap-stabilizing SMC states at high-risk sites. The TGF-β paradox in an inflamed atherosclerotic artery. Smooth muscle “conductor” inside an atherosclerotic artery, confronted with a chaotic TGF-β signal that can drive either repair (capped plaque) or destruction (ulcerated core), illustrating context-dependent TGF-β effects on SMC behavior. Conceptual schematic created in Adobe Photoshop and Illustrator with AI-assisted tools; no experimental or patient data were used or altered