Discoidin Domain Receptor-1 Regulates Calcific Extracellular Vesicle Release in Vascular Smooth Muscle Cell Fibrocalcific Response via Transforming Growth Factor-β Signaling

OBJECTIVE—Collagen accumulation and calcification are major determinants of atherosclerotic plaque stability. Extracellular vesicle (EV)–derived microcalcifications in the collagen-poor fibrous cap may promote plaque rupture. In this study, we hypothesize that the collagen receptor discoidin domain receptor-1 (DDR-1) regulates collagen deposition and release of calcifying EVs by vascular smooth muscle cells (SMCs) through the transforming growth factor-β (TGF-β) pathway. APPROACH AND RESULTS—SMCs from the carotid arteries of DDR-1 mice and wild-type littermates (n=5–10 per group) were cultured in normal or calcifying media. At days 14 and 21, SMCs were harvested and EVs isolated for analysis. Compared with wild-type, DDR-1 SMCs exhibited a 4-fold increase in EV release (P