Vascular Smooth Muscle TRPV4 (Transient Receptor Potential Vanilloid Family Member 4) Channels Regulate Vasoconstriction and Blood Pressure in Obesity

Background: Vascular endothelium and smooth muscle work together to keep the balance of vasomotor tone and jointly maintain vascular homeostasis. Ca 2+ -permeable ion channel TRPV4 (transient receptor potential vanilloid family member 4) in endothelial cells regulates endothelium-dependent vasodilation and contraction in various states. However, how vascular smooth muscle cell TRPV4 (TRPV4 SMC ) contributes to vascular function and blood pressure regulation in physiological and pathologically obese condition has not been fully studied. Methods: We generated smooth muscle TRPV4-deficient mice and developed diet-induced obese mice model and analyzed the role of TRPV4 SMC in intracellular Ca 2+ ([Ca 2+ ] i ) regulation and vasoconstriction. Vasomotor changes of mouse mesenteric artery were measured by wire, and pressure myography. [Ca 2+ ] i were measured by fluo-4 staining. Blood pressure was recorded by telemetric device. Results: Vascular TRPV4 SMC played different roles in regulating vasomotor tone than endothelial TRPV4 due to their different features of [Ca 2+ ] i regulation. Loss of TRPV4 SMC attenuated U46619- and phenylephrine-induced contraction, suggesting its involvement in regulating vascular contractility. Mesenteric arteries from obese mice showed SMC hyperplasia, suggesting an increased level of TRPV4 SMC . Loss of TRPV4 SMC did not influence the development of obesity but protected mice from obesity-induced vasoconstriction and hypertension. In arteries deficient in SMC TRPV4, SMCs F-actin polymerization and RhoA dephosphorylation were attenuated under contractile stimuli. Moreover, SMC-dependent vasoconstriction was inhibited in human resistance arteries with TRPV4 inhibitor application. Conclusions: Our data identify TRPV4 SMC as a regulator of vascular contraction in both physiological states and pathologically obese mice. TRPV4 SMC contributes to the ontogeny of vasoconstriction and hypertension induced by TRPV4 SMC over-expression in obese mice mesenteric artery.