From smooth to 'breaking bad': vascular smooth muscle cell phenotypic switching at the heart of plaque vulnerability

Atherosclerosis persists despite LDL-lowering therapies, highlighting lipid-independent drivers of disease. This review examines vascular smooth muscle cell (VSMC) plasticity as a central determinant of plaque progression and stability and evaluates emerging therapeutic strategies targeting VSMC phenotypic transitions.

VSMCs exhibit marked phenotypic plasticity, contributing to up to 50% of plaque foam cells and generating diverse states including macrophage-like, fibromyocyte, osteogenic, and intermediate populations. Key regulators such as Krüppel-like factor 4 (KLF4) and octamer-binding transcription factor 4 (OCT4) govern transitions between stabilising α-smooth muscle actin-positive (ACTA2 + ) cap-forming and destabilising lectin galactoside-binding soluble 3-positive (LGALS3 + ) inflammatory phenotypes. VSMC-derived foam cells display impaired cholesterol efflux and efferocytosis. Epigenetic reprogramming and oncogenic-like signalling, including nuclear factor kappa B (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), and mitogen-activated protein kinase (MAPK), underpin these changes. Emerging therapies include microRNA-based targeting of KLF4, chimeric antigen receptor regulatory T cells directed against oxidised LDL, nanoparticle systems targeting osteopontin, and fibroblast activation protein (FAP)-directed strategies.

VSMC plasticity integrates inflammatory and epigenetic signals to drive plaque evolution. Targeting specific VSMC states offers a precision medicine approach to stabilise plaques while preserving vascular integrity.