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

Abstract

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.

Milestone Papers on Signal Transduction Mechanisms of Hypertension and Its Complications

“…Lending further credence to these findings, VSMCs obtained from human paraspinal muscles showed significantly higher phenylephrineactivated TRPV4 currents and smaller TRPV4-activated BK currents in hypertensive subjects compared with normotensive individuals. 66 Therefore, an imbalance in function among the constrictor and dilator pools of VSMC TRPV4 favoring a higher α1AR-PKCα-TRPV4 activity could trigger hypertension (see additional discussion about TRPC and TRPV4 channels in the Supplemental Material [96][97][98][99][100][101] ).…”

Vascular smooth muscle TRPV4 channel: a promising therapeutic target for salt-induced hypertension?

“…In addition to the pathophysiological involvement of EC TRPV4 channels in hypertension, emerging evidence sheds light on the role of VSMC TRPV4 channels in vasoconstriction and blood pressure elevation in some models of hypertension using cell-specific TRPV4 knockout mice [6,7]. For example, in mesenteric arteries from Ang IIinfused hypertensive mice, VSMC TRPV4 channels contribute to blood pressure elevation through two distinct mechanisms of action: an elevated α1 adrenergic receptor/ protein kinase Cα/TRPV4-mediated vasoconstriction and an impaired TRPV4/large conductance Ca 2+ -activated K + channels mediated vasorelaxation [6].…”

“…For example, in mesenteric arteries from Ang IIinfused hypertensive mice, VSMC TRPV4 channels contribute to blood pressure elevation through two distinct mechanisms of action: an elevated α1 adrenergic receptor/ protein kinase Cα/TRPV4-mediated vasoconstriction and an impaired TRPV4/large conductance Ca 2+ -activated K + channels mediated vasorelaxation [6]. Moreover, in mesenteric arteries from high-fat diet-induced obese mice, VSMC TRPV4 channels contribute to blood pressure elevation by promoting actin cytoskeleton polymerization through an activation of small GTPase Rho [7].…”

“…Secondly, the endogenous activator of aortic VSMC TRPV4 channels in salt-induced hypertension is not explored in the present study. While VSMC TRPV4 channels in mouse mesenteric resistance arteries are activated by α1-adrenergic receptor signaling in Ang II-induced hypertension [6] and by mechanical force in high-fat diet-induced hypertension [7], it is unknown whether mechanisms contribute to the activation of VSMC TRPV4 channels during salt-induced hypertension in an elastic artery such as the aorta. Finally, caution should be exercised in that the treatment of mice with a concomitant intake of a high-salt diet and N-nitro-L-arginine (a NO synthase inhibitor), as in the present study, may render aortic VSMC vulnerable to vasoconstrictor stimuli; under this specific treatment condition, endothelium-dependent NO production should be severely diminished, and therefore, would be expected to result in facilitation of the VSMC TRPV4 channel-mediated aortic contraction.…”