Matrix Stiffening Induces Endothelial Dysfunction Via the TRPV4/microRNA-6740/endothelin-1 Mechanotransduction Pathway.

Vascular stiffening is associated with the prognosis of cardiovascular disease (CVD). Endothelial dysfunction, as shown by reduced vasodilation and increased vasoconstriction,not only affects vascular tone, but also accelerates progression of CVD. However, the precise effect of vascular stiffening on endothelial function and its mechanism are still unclear. In this study, we found that increasing substrate stiffness promoted endothelin-1 (ET-1) expression and inhibited endothelial nitric oxide synthase expression in human umbilical vein endothelial cells. Additionally, miR-6740-5p was identified as a stiffness-sensitive microRNA, which was down regulated by a stiff substrate, and subsequently resulted in increased ET-1 expression.Furthermore, we found that substrate stiffening reduced expression and activity of the calcium channel TRPV4, which subsequently enhanced ET-1 expression by inhibiting miR-6740-5p. Finally, analysis of clinical plasma samples showed that plasma miR-6740-5p levels inpatients with carotid atherosclerosis were significantly lower than those in healthy people.Taken together, our findings show a novel mechanically regulated TRPV4/miR-6740/ET-1signaling axis by which substrate stiffness affects endothelial function. Our findings suggest that vascular stiffening induces endothelial dysfunction, and thereby accelerates progression of CVD. Furthermore, this study indicated that endothelial dysfunction induced by improper biophysical cues of cardiovascular implants may be an important reason for occurrence of complications for cardiovascular implants.