Vascular Smooth Muscle Cell Plasticity in Atherosclerosis: From Macrophage-like Transdifferentiation to Therapeutic Targeting

Atherosclerosis remains the leading cause of cardiovascular mortality worldwide. Vascular smooth muscle cells (VSMCs) were long regarded as passive structural elements of the arterial wall, but they are now recognized as highly plastic cells capable of transdifferentiating into macrophage-like cells (MLCs). This conversion promotes plaque inflammation, matrix degradation, and necrotic core expansion, yet the mechanisms that control it remain poorly defined. This review synthesizes current understanding of the multilayered regulatory networks that govern VSMC-to-MLC transdifferentiation. These networks couple upstream signaling through MAPK, Notch, TGF-β, and PI3K/AKT to master transcription factors such as KLF4, IRF7, and ZEB2. They further extend to epigenetic mechanisms encompassing DNA methylation, histone modifications, non-coding RNAs, and metabolic reprogramming involving cholesterol efflux and lipophagy. We then assess therapeutic strategies that prevent or reverse this conversion, including miRNA replacement, kinase inhibition, LXR activation and autophagy induction. We further highlight unresolved questions on MLC heterogeneity, reversibility, and targeted delivery, outlining priorities for translating these insights into clinical benefit.