Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation. Commentary

Local vasodilation in response to hypoxia is a fundamental physiologic response ensuring oxygen delivery to tissues under metabolic stress. Recent studies identify a role for the red blood cell (RBC), with hemoglobin the hypoxic sensor. Herein, we investigate the mechanisms regulating this process and explore the relative roles of adenosine triphosphate, S-nitrosohemoglobin, and nitrite as effectors. We provide evidence that hypoxic RBCs mediate vasodilation by reducing nitrite to nitric oxide (NO) and ATP release. NO dependence for nitrite-mediated vasodilation was evidenced by NO gas formation, stimulation of cGMP production, and inhibition of mitochondrial respiration in a process sensitive to the NO scavenger C-PTIO. The nitrite reductase of hemoglobin is modulated by heme deoxygenation and heme redox potential, with maximal observed at 50% hemoglobin oxygenation (P 5 0 ). Concomitantly, vasodilation is initiated at the P 5 0 , suggesting that oxygen sensing by hemoglobin is mechanistically linked to nitrite reduction and stimulation of vasodilation. Mutation of the conserved β93cys residue decreases the heme redox potential (ie, decreases E 1 / 2 ), an effect that increases nitrite reductase and vasodilation at any given hemoglobin saturation. These data support a function for RBC hemoglobin as an allosterically and redox-regulated nitrite reductase whose enzyme activity couples hypoxia to increased NO-dependent blood flow.