Senescence: An Overlooked VSMC Phenotype and Therapeutic Opportunity?

Vascular smooth muscle cells (VSMCs) modulate their phenotype from a quiescent, contractile cell to a dedifferentiated, synthetic fibroproliferative cell in response to injury and cardiovascular risk factors. Senescence is a recognized phenotypically distinct cellular state characterized by cell cycle arrest and activation of the p16 and p53 damage response pathway and expression of the senescence-associated secretory phenotype. Low levels of senescence in healthy arteries contribute to vascular homeostasis by ensuring that only healthy VSMCs compose the artery, but they are not intended to be a persistent cellular component of the artery. However, when discussing VSMC phenotype modulation into foam-like cells, macrophages, mesenchymal cells, fibroblasts, adipocytes, and other VSMC-like cells, senescence is rarely included. This raises an intriguing question: can senescence be recognized as a phenotypic state of VSMCs? As understanding SMC phenotypic switching is crucial for developing therapies that can prevent and treat cardiovascular diseases, so is understanding mechanisms of senescence, and targeting the mechanisms that regulate this modulation could be a promising approach for managing conditions such as atherosclerosis, arterial calcification, and aortic aneurysms. This review aims to summarize recent findings about the molecular mechanisms of VSMC senescence and compare similarities and contrasts with the mechanisms known to regulate VSMC phenotype plasticity. Comparison of transcriptomic databases compelled us to also raise the interesting question: if VSMC can regain their contractile phenotype, can they also be coaxed to exit the senescent state and return to the contractile VSMC phenotype? We posit that senescent VSMCs may not be an end point but rather an intermediate or inflection point in VSMC cell fate decision.