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Figure 5. Young, healthy vascular smooth muscle cells (VSMCs) have a contractile phenotype and a healthy extracellular matrix (ECM), which undergoes turnover and remodeling to maintain its compliance and regulate vascular tone and integrity. VSMCs undergoing senescence alter the composition and stiffness of the ECM, increasing collagen and fibronectin deposition and decreasing elastin. Senescent VSMCs secrete more small extracellular vesicles (sEVs), which promote both calcification and amyloid aggregation and deposition. There is increased endosomal activity and formation of multivesicular endosomes (MVE) which contain sEVs that are degraded by lysosomes or released by binding to the membrane. sEVs from senescent VSMCs contain more medin in a fibrillar form and can accelerate its accumulation as fibrils in the ECM. Senescent sEVs also contain more calcium and annexins, which enhance mineralization. What triggers sEVs to either mineralize or aggregate amyloid is unknown. (Created with BioRender.com)