Role and mechanisms of vascular smooth muscle cell phenotypic transition in diabetic macrovascular complications

Abstract Diabetic macrovascular complications, as one of the leading causes of mortality in diabetic patients, are characterized by insidious onset and high residual risk. Effective prevention and treatment of diabetic macrovascular injury remain critical clinical challenges, necessitating the development of novel therapeutic strategies targeting this complication. Although recent studies have demonstrated that vascular remodeling driven by the phenotypic transition of vascular smooth muscle cells (VSMCs) plays a pivotal role in this process, and increasing attention has been paid to the metabolic pathways and mechanosensitive signaling pathways of VSMCs, the underlying molecular mechanisms remain incompletely elucidated. This review summarizes metabolic reprogramming in VSMCs in diabetes and its impact on vascular remodeling systematically, with a focus on elucidating the core mechanisms of endothelial-VSMC crosstalk, pathological characteristics of VSMCs phenotypic transition during different stages of atherosclerosis (AS), and potential diversified strategies such as the application of microRNAs, extracellular vesicle targeting techniques, and targeted protein regulation. Current evidence indicates that precise modulation of the metabolic-mechanical coupling network in VSMCs can significantly attenuate the progression of atherosclerotic plaques and enhance plaque stability. However, clinical translation remains challenged by insufficient targeting specificity and mechanistic complexity. Future studies should integrate multi-omics technologies with biomimetic models to further optimize therapeutic strategies.