Integration of Vascular Smooth Muscle Cell Phenotypic Switching and Senescence

Abstract: Cardiovascular diseases are life-threatening conditions with multifactorial causes. As the most abundant cells in the vascular wall, vascular smooth muscle cells (VSMCs) play a crucial role in regulating vascular tone. Under physiologic conditions, VSMCs predominantly demonstrate a contractile phenotype. However, this phenotype can be altered in response to microenvironmental stimuli, particularly during injury or pathologic conditions. We performed a systematic literature review to examine the phenotypic switching of VSMCs from a contractile state to a dedifferentiated state, and the role of senescence in VSMC dysfunction. Special attention was given to the impact of microenvironmental stress on VSMCs transdifferentiation into multiple phenotypes, including macrophage-like cells, foam cells, and mesenchymal stem cells. Prolonged or excessive phenotypic switching of VSMCs leads to cellular senescence, characterized by decreased proliferative capacity, increased secretion of inflammatory factors (senescence-associated secretory phenotype), and a tendency toward calcification. Senescent VSMCs undergo transdifferentiation into multiple phenotypes, which promote arterial calcification and fibrosis, thereby exacerbating cardiovascular disease progression. Emerging evidence reveals that VSMC phenotypic switching and senescence share common molecular pathways, offering new opportunities for developing dual-target therapies against age-related cardiovascular diseases by simultaneously modulating cellular plasticity and aging processes.