Targeting Vascular Smooth Muscle Cell Senescence for Cardiovascular Pharmacology: Mechanisms and Therapeutic Perspectives

Vascular smooth muscle cells (VSMCs) play a central role in maintaining vascular tone, structural integrity, and adaptive remodeling. With aging and chronic cardiometabolic stress, however, VSMCs undergo senescence driven by telomere attrition, oxidative stress, persistent DNA-damage signaling, and dysregulation of the p53/p21 and p16/Rb pathways. This transition is accompanied by acquisition of a senescence-associated secretory phenotype (SASP), which promotes inflammation, extracellular matrix remodeling, calcification and vascular stiffening. Together, these accelerate atherosclerosis, hypertension, aneurysm formation, and related vasculopathies. Growing evidence identifies VSMC senescence as a promising therapeutic entry point for cardiovascular drug discovery. Emerging strategies include senolytics, senomorphics, metabolic modulators, and molecular reprogramming approaches designed to either eliminate senescent cells or attenuate their pathogenic secretome and downstream signaling networks. In this review, the molecular basis of VSMC senescence, its contribution to major vascular disorders, and the therapeutic landscape targeting senescence-associated pathways are discussed, with emphasis on translational opportunities and current barriers to clinical application. A clearer understanding of VSMC senescence may inform the development of mechanism-based interventions to limit vascular dysfunction and age-related cardiovascular disease.