Cellular and Molecular Mechanisms of VSMC Phenotypic Switching in Type 2 Diabetes

Vascular smooth muscle cells (VSMCs) are a major cell type in the arterial wall responsible for regulating vascular homeostasis. Under physiological conditions, VSMCs reside in the medial layer of the arteries, express elevated levels of contractile proteins, regulate vascular tone, and provide mechanical strength and elasticity to the blood vessel. In response to obesity, hyperglycemia, and insulin resistance, critical pathogenic hallmarks of Type 2 diabetes (T2D), VSMCs undergo a phenotypic transformation, adopting new phenotypes with increased proliferative (synthetic), inflammatory (macrophage-like), or bone-like (osteogenic) properties. While crucial for normal repair and vascular adaptation, VSMC phenotypic plasticity is a key driver for the development and progression of macrovascular complications associated with T2D. Despite advances in lineage tracing and multi-omics profiling that have uncovered key molecular regulators of VSMC phenotypic switching in vasculopathy, our understanding of the cellular and molecular mechanisms underlying VSMC transformation into diseased phenotypes in T2D remains incomplete. This review will provide a holistic summary of research from the past 15 years, with a focus on the signaling pathways and transcriptional regulators that govern VSMC phenotypic transition in response to obesity, hyperglycemia, and insulin resistance. We examine the integrated molecular mechanisms that orchestrate VSMC fate reprogramming in T2D and highlight the dynamic interplay among diverse signaling and transcriptional networks. Emphasis is placed on how these interconnected pathways collectively influence VSMC behavior and contribute to the pathogenesis of T2D-associated atherosclerosis.