Matrix stiffening induces endothelial dysfunction via the TRPV4/microRNA-6740/endothelin-1 mechanotransduction...

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 the progression of CVD. However, the precise effect of vascular stiffening on endothelial function and its mechanism is unclear and a possible underlying has not been determined. 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 downregulated by a stiff substrate, resulting in increased ET-1 expression. Furthermore, we found that substrate stiffening reduced the 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 in patients with carotid atherosclerosis were significantly lower than those in healthy people. Taken together, our findings show a novel mechanically regulated TRPV4/miR-6740/ET-1 signaling axis by which substrate stiffness affects endothelial function. Our findings indicate that vascular stiffening induces endothelial dysfunction, thereby accelerating progression of CVD. Furthermore, this study indicates that endothelial dysfunction induced by improper biophysical cues from cardiovascular implants may be an important reason for complications arising from the use of cardiovascular implants. STATEMENT OF SIGNIFICANCE: Cardiovascular disease is the leading cause of morbidity and mortality worldwide. The incidence of cardiovascular disease is accompanied by increased vascular stiffness. Our work indicated that increased vascular stiffness accelerates the development of cardiovascular disease by inducing endothelial dysfunction, which is a key contributor to the pathogenesis of cardiovascular disease. In addition, we identified a novel underlying molecular pathophysiological mechanism by which increased stiffness induce endothelial dysfunction. Our work could help determine the pathogenesis of cardiovascular disease induced by biomechanical factors.