Fig. 2

VSMCs phenotype switching and vascular aging. In vascular aging, environmental damage factors trigger mitochondrial dysfunction, telomere attrition, DNA damage, epigenetic changes, oxidative stress, impaired resistance to molecular stressors, chronic low-grade inflammation, genomic instability in VSMCs. Once these damage factors accumulate to a certain extent and cannot be repaired, VSMCs switch to senescence­associated secretory phenotype (SASP). The impaired endothelial barrier caused by vascular aging accelerated the environmental damage on VSMCs. Meanwhile, overproliferation of VSMCs also contributes to SASP. SASP-VSMCs became irregular in morphology and highly expressed integrin protein, focal adhesion protein, and cytoskeleton protein. Cytoskeleton actin was connected to elastin and collagen in ECM through integrin-based focal adhesion, delivering anchoring force and adhesion force. When the above protein is up-regulated, not only increases the VSMCs stiffness but also increases the interaction between ECM and VSMCs, leading to increased vascular stiffness. SASP-VSMCs secrete a large amount of MMPs for decomposing elastin into fragments, synthesize collagen, and promote its crosslinking. This process increases ECM stiffness and decreases ECM elasticity. On the other hand, the high expression of RUNX2, BMP2, and ALP in senescent VSMCs makes it susceptible to switch to osteogenic VSMCs under high calcium or phosphorus environment. Osteogenic VSMCs release calcium phosphate enriched vesicles to promote VC. VEC, vascular endothelial cell; SASP, senescence­associated secretory phenotype; RUNX2, runt-related transcription factor 2; BMP2, bone morphogenetic protein-2; ALP, alkaline phosphatase; VC, vascular calcification