Endothelial TRPV4 Channel Function is Impaired in Pulmonary Arterial Hypertension

Abstract

Endothelial dysfunction contributes to the pathogenesis of pulmonary arterial hypertension (PAH) by reducing arterial vasodilation. Endothelium‐dependent vasodilation is an important regulator of pulmonary vascular resistance (PVR) and overall pulmonary arterial pressure (PAP). We recently identified endothelial TRPV4 (transient receptor potential vanilloid 4) channels as important regulators of vasodilation in pulmonary arteries (PAs), and showed that unitary Ca2+ influx events through TRPV4 channels, termed TRPV4 sparklets, activate endothelial nitric oxide synthase (eNOS) to cause vasodilation. Reduced NO bioavailability is a hallmark of endothelial dysfunction in PAH. However, the mechanisms underlying reduced NO bioavailability in PAH are not well understood. We hypothesized that impairment of TRPV4 channel function attenuates NO release in PAH. PAH was induced in mice using three‐week chronic hypoxia (CH) and Sugen 5416 + CH models. Mouse right ventricular pressures (RVP) were measured as an indicator of PAP. RVP was significantly higher in TRPV4−/− mice when compared to the control mice after three weeks of CH. High‐speed Ca2+ imaging was used to analyze TRPV4 sparklets in the native endothelium from resistance‐sized, fourth‐order PAs. Vascular diameter studies were performed on isolated, pressurized (15 mmHg), small PAs. Ca2+ imaging studies were also performed in PAs obtained from control and PAH patients. In CH and Sugen 5416 + CH models, TRPV4 sparklet activity and TRPV4 channel‐dependent vasodilation were significantly lower compared to normoxic control mice. However, TRPV4 mRNA expression and immunofluorescence were not altered in both mouse models of PAH, suggesting an impairment in the regulation of channel function rather than channel expression. TRPV4 sparklet activity was also consistently lower in PAs from PAH patients, when compared to control patients. Elevated levels of superoxide radicals have been shown to contribute to the development of PAH. Superoxides can react with NO to form peroxynitrite (PN). A PN scavenger, uric acid, restored TRPV4 channel activity in CH mice. We, therefore, hypothesized that PN‐induced impairment of TRPV4‐dependent Ca2+ signaling inhibits endothelial function in PAH. Indeed, PN attenuated TRPV4 sparklet activity in a reversible manner. Our results support the concept that PN‐induced regulation of TRPV4‐dependent Ca2+ signaling may contribute to the development of PAH. Moreover, altered TRPV4 channel activity may contribute to the reduced NO bioavailability in PAH.Support or Funding Information1R56HL138496, 5R00HL121484, 17PRE33660762This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.