Nitrite Regulates Hypoxic Vasodilation via Myoglobin-Dependent Nitric Oxide Generation
Background—Hypoxic vasodilation is a physiological response to low oxygen (O2) tension that increases blood supply to match metabolic demands. While this response has been characterized for more than 100 years, the underlying hypoxic sensing and effector signaling mechanisms remain uncertain. We have shown that deoxygenated myoglobin (deoxyMb) in the heart can reduce nitrite to nitric oxide (NO•) and thereby contribute to cardiomyocyte NO• signaling during ischemia. Based on recent observations that Mb is expressed in the vasculature of hypoxia-tolerant fish, we hypothesized that endogenous nitrite may contribute to physiological hypoxic vasodilation via reactions with vascular Mb to form NO•.
Methods and Results—We here show that Mb is expressed in vascular smooth muscle and contributes significantly to nitrite-dependent hypoxic vasodilation in vivo and ex vivo. The generation of NO• from nitrite reduction by deoxyMb activates canonical soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) signaling pathways. In vivo and ex vivo vasodilation responses, the reduction of nitrite to NO• and the subsequent signal transduction mechanisms were all significantly impaired in mice without myoglobin (Mb-/-). Hypoxic vasodilation studies in Mb, endothelial and inducible NO synthase knockout models (eNOS-/-, iNOS-/-) suggest that only Mb contributes to systemic hypoxic vasodilatory responses in mice.
Conclusions—Endogenous nitrite is a physiological effector of hypoxic vasodilation. Its reduction to NO• via the heme globin Mb enhances blood flow and matches O2 supply to increased metabolic demands under hypoxic conditions.
- Received December 13, 2011.
- Accepted May 22, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited