Deficiency of TRPV4 abolishes shear stress‐induced vasodilation in mice.

In endothelial sensing of shear stress, the Ca2+‐permeable TRPV4 channel was proposed a candidate mechanosensor. Using TRPV4−/− mice, we investigated whether the absence of endothelial TRPV4 alters shear‐stress‐induced vasodilation. Loss of the TRPV4 protein and function was confirmed by IHC and electrophysiology in endothelium of TRPV4−/− mice. Agonist‐ and shear stress‐induced vasodilation was determined by pressure myography in carotid artery (CA) of TRPV4−/− and TRPV4+/+ mice (WT). In WT CAEC, TRPV4 was activated by the pharmacological TRPV4‐opener 4alphaPDD, arachidonic acid (AA), and by hypotonic cell swelling (HTS). In CAEC of TRPV4−/−, 4alphaPDD did not produce currents and currents in response to AA and HTS were greatly reduced. 4alphaPDD elicited a robust and strictly endothelium‐dependent vasodilation in WT mice, again strikingly absent in TRPV4−/− mice. Shear stress‐induced vasodilation was present in WT, but was eliminated in TRPV4−/− mice. Flow‐induced vasodilation was significantly reduced in TRPV4−/− vs. WT mice. In conclusion, loss of TRPV4 abolishes shear stress‐induced vasodilation. Thus, Ca2+‐influx through endothelial TRPV4 channels is a critical mechanism contributing to endothelial mechanotransduction.