The DOI matches its Crossref record; 58 of the 58 references it cites were found in a registry or an index.
Nitrite Regulates Hypoxic Vasodilation via Myoglobin-Dependent Nitric Oxide Generation
Open accessAbstract
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·. METHODS AND 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.
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In the citing paper
“Inhaled NO induces vasodilation in PAH and is capable of reversing hypoxic pulmonary vasoconstriction[139–141].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [141]
In the citing paper
“Nitrite as a reservoir can be further reduced to NO via numerous pathways in blood and tissue, and this process is indeed accelerated under hypoxic conditions.44 -47”
From Dietary nitrate supplementation improves revascularization in chronic ischemia (2012) · cites this paper as [44]
In the citing paper
“Nitrite may form NO either via deoxyhemoglobin (deoxyHb, Fe II Hb) [80,81], deoxymyoglobin [82] or xanthine oxidoreductase (XOR)-mediated reduction [83], or via spontaneous [84] and carbonic anhydrase-facilitated disproportionation [85].”
From On the chemical biology of the nitrite/sulfide interaction (2015) · cites this paper as [82]
In the citing paper
“Mb-mediated nitrite reduction has been reported to be important in both cardiomyocytes [55] and smooth muscle [56].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [56]
In the citing paper
“As discussed below, a functional role for myoglobin in nitrite reduction and signaling is strongly supported by multiple studies in myoglobin knockout mice showing a reduction in nitrite mediated effects on mitochondrial respiration, cardiac function, ischemia reperfusion cytoprotection, and systemic hypoxic vasodilation [54–56].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [56]
In the citing paper
“Smooth muscle myoglobin has also been implicated in modulating nitrite-dependent increases in blood flow [56, 113].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [56]
In the citing paper
“In addition, NO formation from administered nitrite and associated vasorelaxation were much higher in wild type mice compared to knockouts .[56]”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [56]
In the citing paper
“Totzeck and coworkers conducted in vitro and in vivo experiments supporting a role for smooth muscle Mb in nitrite mediated vasodilation using wild type and Mb knockout mice [56].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [56]
In the citing paper
“NO production from nitrite in aorta were greatly attenuated in the knockout compared to wild type and inhibition of XOR did not affect NO production in the wild type [56]”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [56]
In the citing paper
“A role for nitrite reduction by NOS was not supported by experiments using NOS knockout mice [56].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [56]
In the citing paper
“NO production from nitrite in aorta were greatly attenuated in the knockout compared to wild type and inhibition of XOR did not affect NO production in the wild type [56]”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [56]
In the citing paper
“Blood pressure from wild type mice was substantially more reduced compared to Mb knockout mice when exposed to hypoxia in vivo [56].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [56]
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Citations
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Self-citationEffects of Dietary Nitrate on Blood Pressure in Healthy Volunteers
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Circulating Nitrite Contributes to Cardioprotection by Remote Ischemic Preconditioning
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Metadata
- Authors
- Totzeck, M., Hendgen-Cotta, U. B., Luedike, P., Berenbrink, M., Klare, J. P., Steinhoff, H.-J., Semmler, D., Shiva, S., Williams, D., Kipar, A., Gladwin, M. T., Schrader, J., Kelm, M., Cossins, A. R., & Rassaf, T.
- Affiliations
- University of Liverpool (GB)
- From the Department of Medicine, Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Hospital Duesseldorf, Duesseldorf, Germany (M.T., U.B.H.-C., P.L., D.S., M.K., T.R.); Institute of Integrative Biology (M.B., D.W., A.R.C.) and Department of Veterinary Pathology (A.K.), University of Liverpool, Liverpool, United Kingdom; Department of Physics, University Osnabrueck, Osnabrueck, Germany (J.P.K., H.S.); Departments of Pharmacology and Chemical Biology (S.S.) and...
- ORCID
- Venue
- Circulation
- Published
- 2012-07-17
- Volume
- 126
- Issue
- 3
- Pages
- 325-334
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC3410747
- OpenAlex
- W2165218367
- Cited by
- 202
- References
- 58
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 7 · 2023: 6 · 2022: 10 · 2021: 6 · 2020: 15 · 2019: 16 · 2018: 13 · 2017: 21 · 2016: 19 · 2015: 17 · 2014: 27 · 2013: 28 · 2012: 5
- FWCI
- 11.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (RA969/4-2])
- Deutsche Herzstiftung
- Deutsche Gesellschaft für Kardiologie-Herz und Kreislaufforschung.
- National Institutes of Health
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council
- National Heart, Lung, and Blood Institute (R01HL096973, P01HL103455, R01HL098032)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Keywords
- hypoxic vasodilation, nitrite, nitric oxide, myoglobin, vascular smooth muscle, soluble guanylate cyclase, cGMP signaling, hypoxia sensing, inducible nitric oxide synthase, endothelial nitric oxide synthase, oxygen supply and demand
- MeSH terms
- Soluble Guanylyl Cyclase, Adaptation, Physiological, Animals, Hypoxia, Cardiac Output, Guanylate Cyclase, Mice, Mutant Strains, Muscle, Smooth, Vascular, Myoglobin, Nitric Oxide, Nitrites, Oxygen, Vasodilation, Signal Transduction, Receptors, Cytoplasmic and Nuclear, Mice, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III
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