Energetic Decoding of VSMC Plasticity: Metabolic Reprogramming and Phenotypic Switching.

Phenotypic switching of vascular smooth muscle cells (VSMCs) constitutes a pivotal event in the initiation and progression of various vascular diseases, including vascular calcification, atherosclerosis, aneurysm, and pulmonary arterial hypertension. The transition from a contractile to a synthetic phenotype is commonly characterized by increased proliferation, migration, and extracellular matrix synthesis, thus generating substantial bioenergetic demands. In recent years, accumulating evidence has indicated that metabolic reprogramming has emerged as a key regulatory dimension of VSMC plasticity. In this review, we systematically summarize the regulatory mechanisms by which metabolic reprogramming governs VSMC phenotypic switching, focusing mainly on glucose, lipid, and amino acid metabolism, while also discussing selected metabolite-derived signaling events and disease-context-specific metabolic patterns. We particularly emphasize how metabolic alterations collectively help shape VSMC fate through the integrated effects of energy supply, metabolic intermediates, and their associated signaling networks. Our aim is to establish a systematic theoretical framework linking metabolic reprogramming to VSMC phenotypic switching, thereby providing new insights into the mechanisms underlying vascular remodeling and laying a theoretical foundation for the development of metabolism-targeted therapeutic strategies.