Hemoglobin α/eNOS Coupling at Myoendothelial Junctions Is Required for Nitric Oxide Scavenging During Vasoconstriction
Open accessAbstract
Objective—: Hemoglobin α (Hb α) and endothelial nitric oxide synthase (eNOS) form a macromolecular complex at myoendothelial junctions; the functional role of this interaction remains undefined. To test if coupling of eNOS and Hb α regulates nitric oxide signaling, vascular reactivity, and blood pressure using a mimetic peptide of Hb α to disrupt this interaction. Approach and Results—: In silico modeling of Hb α and eNOS identified a conserved sequence of interaction. By mutating portions of Hb α, we identified a specific sequence that binds eNOS. A mimetic peptide of the Hb α sequence (Hb α X) was generated to disrupt this complex. Using in vitro binding assays with purified Hb α and eNOS and ex vivo proximity ligation assays on resistance arteries, we have demonstrated that Hb α X significantly decreased interaction between eNOS and Hb α. Fluorescein isothiocyanate labeling of Hb α X revealed localization to holes in the internal elastic lamina (ie, myoendothelial junctions). To test the functional effects of Hb α X, we measured cyclic guanosine monophosphate and vascular reactivity. Our results reveal augmented cyclic guanosine monophosphate production and altered vasoconstriction with Hb α X. To test the in vivo effects of these peptides on blood pressure, normotensive and hypertensive mice were injected with Hb α X, which caused a significant decrease in blood pressure; injection of Hb α X into eNOS -/- mice had no effect. Conclusions—: These results identify a novel sequence on Hb α that is important for Hb α/eNOS complex formation and is critical for nitric oxide signaling at myoendothelial junctions.
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Endothelial alpha globin regulates NO availability via direct interaction with eNOS.
“Functionally, the endothelial alpha globin was shown to regulate NO availability via direct interaction with eNOS in these cells (171).”
From Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia (2017) · cites this paper as [171]
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Research works printed but not linked: 2
- [8]Sonkusare SK Bonev AD Ledoux J Liedtke W Kotlikoff MI Heppner TJ Hill-Eubanks DC Nelson MT Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function Science 2012 336 597 601 22556255 PMC3715993
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Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia
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Self-citation
- Authors
- Straub, A. C., Butcher, J. T., Billaud, M., Mutchler, S. M., Artamonov, M. V., Nguyen, A. T., Johnson, T., Best, A. K., Miller, M. P., Palmer, L. A., Columbus, L., Somlyo, A. V., Le, T. H., & Isakson, B. E.
- Affiliations
- University of Pittsburgh (US)
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2014-12
- Volume
- 34
- Issue
- 12
- Pages
- 2594-2600
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- PMC
- PMC4239174
- OpenAlex
- W2054874617
- Cited by
- 82
- References
- 36
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 5 · 2023: 5 · 2022: 9 · 2021: 12 · 2020: 7 · 2019: 4 · 2018: 4 · 2017: 15 · 2016: 6 · 2015: 3
- FWCI
- 5.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Virginia
- National Institutes of Health (2r01gm087828-06a1)
- National Heart, Lung, and Blood Institute (P01HL101871, R21HL107963, HL-107963, R00HL112904, K99HL112904, U10HL109250, R01HL088554, HL-088554, HL-112904, T32HL007284)
- National Institute of General Medical Sciences (R01-GM087828, GM086457, GM087828, R01GM086457)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK061296, DK-088905, R01DK088905, DK06129611)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Keywords
- endothelial nitric oxide synthase, myoendothelial junctions, nitric oxide scavenging, vasoconstriction, cyclic GMP, blood pressure regulation, protein-protein interaction, peptidomimetics, internal elastic lamina, hypertension, vascular reactivity
- MeSH terms
- Amino Acid Sequence, Animals, Blood Pressure, Cells, Cultured, Computer Simulation, Humans, Intercellular Junctions, Male, Mice, Inbred C57BL, Models, Molecular, Molecular Sequence Data, Nitric Oxide, Recombinant Proteins, Vascular Resistance, Vasoconstriction, Signal Transduction, Mutagenesis, Site-Directed, Conserved Sequence, Mice, Knockout, Myocytes, Smooth Muscle, Endothelial Cells, Mice, Nitric Oxide Synthase Type III, Protein Interaction Domains and Motifs, alpha-Globins
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