Endothelial TRPV4 channel signaling in blood pressure regulation

Impaired endothelium-dependent vasodilation is a hallmark of obesity-induced hypertension. The 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. In this regard, TRPV4 ion channels are a major Ca2+ influx pathway in endothelial cells, and regulatory protein AKAP150 enhances the activity of TRPV4 channels. We show that Ca2+ influx through TRPV4 channels at myoendothelial projections (MEPs) to smooth muscle cells decreases resting blood pressure in non-obese mice, a response that is diminished in obese mice. Counterintuitively, release of the vasodilator molecule NO attenuated endothelial TRPV4 channel activity and vasodilation in obese animals. Increased activities of iNOS and NOX1 enzymes at MEPs in obese mice generated higher levels of NO and superoxide radicals, resulting in increased local peroxynitrite formation and subsequent oxidation of the regulatory protein AKAP150 at cysteine 36, to impair AKAP150-TRPV4 channel signaling at MEPs. Strategies that lowered peroxynitrite levels prevented cysteine 36 oxidation of AKAP150, and rescued endothelial AKAP150-TRPV4 signaling, vasodilation, and blood pressure in obesity. Importantly, peroxynitrite-dependent impairment of endothelial TRPV4 channel activity and vasodilation was also observed in the arteries from obese patients. These data suggest that a spatially restricted impairment of endothelial TRPV4 channels contributes to obesity-induced hypertension, and imply that inhibiting peroxynitrite might represent a strategy for normalizing endothelial TRPV4 channel activity, vasodilation, and blood pressure in obesity.