Locally formed Peroxynitrite inhibits endothelial TRPV4 channels and elevates blood pressure in obesity

Abstract

Impaired endothelium‐dependent vasodilation is a hallmark finding of obesity‐induced hypertension. Recognition that Ca2+ signaling in endothelial cells promotes vasodilation has led to the hypothesis that endothelial Ca2+ signaling is compromised during obesity, but the underlying abnormality is unknown. Here, we show that Ca2+ influx through TRPV4 channels at myoendothelial projections (MEPs) to smooth muscle cells lowers resting blood pressure in non‐obese mice, a response that is diminished in obese mice. Counter‐intuitively, release of nitric oxide (NO) from endothelial cells attenuates TRPV4 channel activity and TRPV4‐mediated vasodilation in the obese animals. Increased activities of iNOS and NOX1 correlated with elevated levels of NO and superoxide radicals at the MEPs in obese mice, ultimately reacting to form peroxynitrite. Subsequent findings revealed that peroxynitrite causes cysteine oxidation of the regulatory protein AKAP150 to inhibit TRPV4 channel activity at the MEPs. TRPV4 channel activity and vasodilation are also impaired in the arteries from obese patients, and are restored by strategies that lower peroxynitrite levels. These data suggest that defective TRPV4 channel–mediated vasodilation may contribute to obesity‐induced hypertension, and imply that inhibiting peroxynitrite may represent a strategy to normalize endothelial TRPV4 channel activity, vasodilation and blood pressure during obesity.Support or Funding InformationHL121484‐01, HL138496