Bioinspired therapeutic platform based on extracellular vesicles for prevention of arterial wall remodeling in hypertension

Arterial stiffness due to the vessel remodeling is closely linked to raised blood pressure,and its physiopathologic mechanism is still not fully understood.We here aimed to explore whether extracellular vesicle(EV)mediated intercellular communication between endothelium and smooth muscle cell contribute to the blood vessel remodeling under hypertension.We here revealed that the arterial endothelial cells robustly secreted EV,which in turn could be circulated and/or directly taken up by the subendothelial smooth muscle cells(SMC).Under hypertension,the EV secretion increased and the miRNA profile changed significantly mainly due to the raised mechanical force and subsequent enhanced reactive oxygen species generation.Among the miRNA cargos in the EV,miR-320d/423-5p were found increased most significantly.In vivo delivery of miR-320d/423-5p mimics via engineered EV increased their expression in arterial vessels,recapitulating the phenotype in hypertension.In contrast,therapeutic delivery of miR-320d/423-5p inhibitors via engineered EV alleviated the phenotype in spontaneous hypertension rat model.Together,we have found that the injured endothelium due to the raised mechanical force in hypertension contributes to the arterial wall remodeling via the secreted EV.Our study has not only provided novel insights on the mechanism of hypertension associated blood vessel wall remodeling,but also shed light on therapeutic intervention of hypertension associated vascular diseases.