lincRNA-p21 drives apoptosis and calcification of vascular smooth muscle cell via small extracellular vesicles under hyperphosphatemic conditions in chronic kidney disease.

Vascular calcification, a major contributor to cardiovascular morbidity, involves pathological osteogenic transdifferentiation of vascular smooth muscle cell (VSMC) under hyperphosphatemic conditions in chronic kidney disease. This study investigates the role of lincRNA-p21 and small extracellular vesicles in phosphate-induced mouse aortic smooth muscle cell (MASMC) calcification. Exposure to phosphate (2.6 mmol/L) triggered time-dependent calcification, characterized by enhanced calcium deposition, endoplasmic reticulum remodeling, and intracellular calcium accumulation (p < 0.05 vs. 24/48-h controls). Concurrently, the expression of osteogenic markers (BGP, OCN, and OPN) and lincRNA-p21 was significantly upregulated, whereas the expression of contractile phenotype-specific markers (SM22α, SM-MHC, and SM α-actin) was markedly down-regulated. This pattern of gene expression was correlated with MASMC osteogenic transdifferentiation. Small extracellular vesicles isolated from phosphate-treated MASMC exhibited elevated lincRNA-p21 levels (p < 0.05) and induced calcification and apoptosis in recipient cells, suggesting small extracellular vesicles-mediated propagation of calcific signals. Functional studies demonstrated that lincRNA-p21 overexpression exacerbated calcification, apoptosis, and osteogenic marker expression, while its knockdown attenuated these effects (p < 0.05). Time-course analyses revealed lincRNA-p21 dynamically regulates small extracellular vesicles secretion, calcium accumulation, and apoptotic pathways, acting as a molecular switch driving phosphate-induced calcification. These findings establish lincRNA-p21 as a critical mediator of MASMC calcification via small extracellular vesicles-dependent mechanisms, offering insights into therapeutic strategies for vascular calcification.