Nitrite regulates hypoxic vasodilation via myoglobin-dependent nitric oxide generation.
BACKGROUND
Hypoxic vasodilation is a physiological response to low oxygen tension that increases blood supply to match metabolic demands. Although this response has been characterized for >100 years, the underlying hypoxic sensing and effector signaling mechanisms remain uncertain. We have shown that deoxygenated myoglobin in the heart can reduce nitrite to nitric oxide (NO·) and thereby contribute to cardiomyocyte NO· signaling during ischemia. On the basis of recent observations that myoglobin is expressed in the vasculature of hypoxia-tolerant fish, we hypothesized that endogenous nitrite may contribute to physiological hypoxic vasodilation via reactions with vascular myoglobin to form NO·.


RESULTS
We show in the present study that myoglobin 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 deoxygenated myoglobin activates canonical soluble guanylate cyclase/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. Hypoxic vasodilation studies in myoglobin and endothelial and inducible NO synthase knockout models suggest that only myoglobin 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 myoglobin enhances blood flow and matches O(2) supply to increased metabolic demands under hypoxic conditions.
Department of Medicine, Division of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Duesseldorf, Germany.
Matthias
M
Totzeck
Ulrike B
UB
Hendgen-Cotta
Peter
P
Luedike
Michael
M
Berenbrink
Johann P
JP
Klare
Heinz-Juergen
HJ
Steinhoff
Dominik
D
Semmler
Sruti
S
Shiva
Daryl
D
Williams
Anja
A
Kipar
Mark T
MT
Gladwin
Juergen
J
Schrader
Malte
M
Kelm
Andrew R
AR
Cossins
Tienush
T
Rassaf
D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D002302:Cardiac Output / Q000502:physiology; D006162:Guanylate Cyclase / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology*; D051379:Mice; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D009211:Myoglobin / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism*; D010100:Oxygen / Q000097:blood; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D014664:Vasodilation / Q000502:physiology*
D009211:Myoglobin; D009573:Nitrites; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D010100:Oxygen