ArticleArteriosclerosis, thrombosis, and vascular biology2014
Hemoglobin α/eNOS coupling at myoendothelial junctions is required for nitric oxide scavenging during vasoconstriction.
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Article in Arteriosclerosis, thrombosis, and vascular biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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58 citing papers in PubMed, 83 citations in OpenAlex.
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- Sickle Trait and Alpha Thalassemia Increase NOS-Dependent Vasodilation of Human Arteries Through Disruption of Endothelial Hemoglobin-eNOS Interactions.Circulation · 2025Article
- Promotion of nitric oxide production: mechanisms, strategies, and possibilities.Frontiers in physiology · 2025Review
- Hemoglobin as an oxygen gasoreceptor.Acta biochimica Polonica · 2025Review
- Nitric oxide modelling and its bioavailability influenced by red blood cells.Journal of the Royal Society, Interface · 2024Article
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- The conducted vasomotor response and the principles of electrical communication in resistance arteries.Physiological reviews · 2024Review
- Hypoxia Dysregulates the Transcription of Myoendothelial Junction Proteins Involved with Nitric Oxide Production in Brain Endothelial Cells.Biomedicines · 2023Article
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- Endothelial alpha globin is a nitrite reductase.Nature communications · 2022Article
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- DIA-Based Proteomic Analysis of Plasma Protein Profiles in Patients with Severe Acute Pancreatitis.Molecules (Basel, Switzerland) · 2022Article
- The role of globins in cardiovascular physiology.Physiological reviews · 2022Review
- Redox-Regulation of α-Globin in Vascular Physiology.Antioxidants (Basel, Switzerland) · 2022Article
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Authors and funding
14 authors at 1 institution in 1 country.
Adam C StraubFrom the Department of Pharmacology and Chemical Biology (A.C.S.) and Heart, Lung, Blood and Vascular Medicine Institute (A.C.S., A.T.N., M.P.M.), University of Pittsburgh, PA; Robert M. Berne Cardiovascular Research Center (J.T.B., M.B., S.M.M., T.J., A.K.B., B.E.I.), Department of Molecular Physiology and Biophysics (M.B., M.V.A., A.V.S., B.E.I.), Deparment of Pediatrics (L.A.P.), Department of Chemistry (L.C.), and Department of Medicine (T.H.L.), University of Virginia, Charlottesville.
Joshua T ButcherFrom the Department of Pharmacology and Chemical Biology (A.C.S.) and Heart, Lung, Blood and Vascular Medicine Institute (A.C.S., A.T.N., M.P.M.), University of Pittsburgh, PA; Robert M. Berne Cardiovascular Research Center (J.T.B., M.B., S.M.M., T.J., A.K.B., B.E.I.), Department of Molecular Physiology and Biophysics (M.B., M.V.A., A.V.S., B.E.I.), Deparment of Pediatrics (L.A.P.), Department of Chemistry (L.C.), and Department of Medicine (T.H.L.), University of Virginia, Charlottesville.
Marie BillaudFrom the Department of Pharmacology and Chemical Biology (A.C.S.) and Heart, Lung, Blood and Vascular Medicine Institute (A.C.S., A.T.N., M.P.M.), University of Pittsburgh, PA; Robert M. Berne Cardiovascular Research Center (J.T.B., M.B., S.M.M., T.J., A.K.B., B.E.I.), Department of Molecular Physiology and Biophysics (M.B., M.V.A., A.V.S., B.E.I.), Deparment of Pediatrics (L.A.P.), Department of Chemistry (L.C.), and Department of Medicine (T.H.L.), University of Virginia, Charlottesville.
Stephanie M MutchlerFrom the Department of Pharmacology and Chemical Biology (A.C.S.) and Heart, Lung, Blood and Vascular Medicine Institute (A.C.S., A.T.N., M.P.M.), University of Pittsburgh, PA; Robert M. Berne Cardiovascular Research Center (J.T.B., M.B., S.M.M., T.J., A.K.B., B.E.I.), Department of Molecular Physiology and Biophysics (M.B., M.V.A., A.V.S., B.E.I.), Deparment of Pediatrics (L.A.P.), Department of Chemistry (L.C.), and Department of Medicine (T.H.L.), University of Virginia, Charlottesville.
Mykhaylo V ArtamonovFrom the Department of Pharmacology and Chemical Biology (A.C.S.) and Heart, Lung, Blood and Vascular Medicine Institute (A.C.S., A.T.N., M.P.M.), University of Pittsburgh, PA; Robert M. Berne Cardiovascular Research Center (J.T.B., M.B., S.M.M., T.J., A.K.B., B.E.I.), Department of Molecular Physiology and Biophysics (M.B., M.V.A., A.V.S., B.E.I.), Deparment of Pediatrics (L.A.P.), Department of Chemistry (L.C.), and Department of Medicine (T.H.L.), University of Virginia, Charlottesville.
Anh T NguyenFrom the Department of Pharmacology and Chemical Biology (A.C.S.) and Heart, Lung, Blood and Vascular Medicine Institute (A.C.S., A.T.N., M.P.M.), University of Pittsburgh, PA; Robert M. Berne Cardiovascular Research Center (J.T.B., M.B., S.M.M., T.J., A.K.B., B.E.I.), Department of Molecular Physiology and Biophysics (M.B., M.V.A., A.V.S., B.E.I.), Deparment of Pediatrics (L.A.P.), Department of Chemistry (L.C.), and Department of Medicine (T.H.L.), University of Virginia, Charlottesville.
Tyler JohnsonFrom the Department of Pharmacology and Chemical Biology (A.C.S.) and Heart, Lung, Blood and Vascular Medicine Institute (A.C.S., A.T.N., M.P.M.), University of Pittsburgh, PA; Robert M. Berne Cardiovascular Research Center (J.T.B., M.B., S.M.M., T.J., A.K.B., B.E.I.), Department of Molecular Physiology and Biophysics (M.B., M.V.A., A.V.S., B.E.I.), Deparment of Pediatrics (L.A.P.), Department of Chemistry (L.C.), and Department of Medicine (T.H.L.), University of Virginia, Charlottesville.
Angela K BestFrom the Department of Pharmacology and Chemical Biology (A.C.S.) and Heart, Lung, Blood and Vascular Medicine Institute (A.C.S., A.T.N., M.P.M.), University of Pittsburgh, PA; Robert M. Berne Cardiovascular Research Center (J.T.B., M.B., S.M.M., T.J., A.K.B., B.E.I.), Department of Molecular Physiology and Biophysics (M.B., M.V.A., A.V.S., B.E.I.), Deparment of Pediatrics (L.A.P.), Department of Chemistry (L.C.), and Department of Medicine (T.H.L.), University of Virginia, Charlottesville.
Megan P MillerFrom the Department of Pharmacology and Chemical Biology (A.C.S.) and Heart, Lung, Blood and Vascular Medicine Institute (A.C.S., A.T.N., M.P.M.), University of Pittsburgh, PA; Robert M. Berne Cardiovascular Research Center (J.T.B., M.B., S.M.M., T.J., A.K.B., B.E.I.), Department of Molecular Physiology and Biophysics (M.B., M.V.A., A.V.S., B.E.I.), Deparment of Pediatrics (L.A.P.), Department of Chemistry (L.C.), and Department of Medicine (T.H.L.), University of Virginia, Charlottesville.
Lisa A PalmerFrom the Department of Pharmacology and Chemical Biology (A.C.S.) and Heart, Lung, Blood and Vascular Medicine Institute (A.C.S., A.T.N., M.P.M.), University of Pittsburgh, PA; Robert M. Berne Cardiovascular Research Center (J.T.B., M.B., S.M.M., T.J., A.K.B., B.E.I.), Department of Molecular Physiology and Biophysics (M.B., M.V.A., A.V.S., B.E.I.), Deparment of Pediatrics (L.A.P.), Department of Chemistry (L.C.), and Department of Medicine (T.H.L.), University of Virginia, Charlottesville.
Linda ColumbusFrom the Department of Pharmacology and Chemical Biology (A.C.S.) and Heart, Lung, Blood and Vascular Medicine Institute (A.C.S., A.T.N., M.P.M.), University of Pittsburgh, PA; Robert M. Berne Cardiovascular Research Center (J.T.B., M.B., S.M.M., T.J., A.K.B., B.E.I.), Department of Molecular Physiology and Biophysics (M.B., M.V.A., A.V.S., B.E.I.), Deparment of Pediatrics (L.A.P.), Department of Chemistry (L.C.), and Department of Medicine (T.H.L.), University of Virginia, Charlottesville.
Avril V SomlyoFrom the Department of Pharmacology and Chemical Biology (A.C.S.) and Heart, Lung, Blood and Vascular Medicine Institute (A.C.S., A.T.N., M.P.M.), University of Pittsburgh, PA; Robert M. Berne Cardiovascular Research Center (J.T.B., M.B., S.M.M., T.J., A.K.B., B.E.I.), Department of Molecular Physiology and Biophysics (M.B., M.V.A., A.V.S., B.E.I.), Deparment of Pediatrics (L.A.P.), Department of Chemistry (L.C.), and Department of Medicine (T.H.L.), University of Virginia, Charlottesville.
Thu H LeFrom the Department of Pharmacology and Chemical Biology (A.C.S.) and Heart, Lung, Blood and Vascular Medicine Institute (A.C.S., A.T.N., M.P.M.), University of Pittsburgh, PA; Robert M. Berne Cardiovascular Research Center (J.T.B., M.B., S.M.M., T.J., A.K.B., B.E.I.), Department of Molecular Physiology and Biophysics (M.B., M.V.A., A.V.S., B.E.I.), Deparment of Pediatrics (L.A.P.), Department of Chemistry (L.C.), and Department of Medicine (T.H.L.), University of Virginia, Charlottesville.
Brant E IsaksonFrom the Department of Pharmacology and Chemical Biology (A.C.S.) and Heart, Lung, Blood and Vascular Medicine Institute (A.C.S., A.T.N., M.P.M.), University of Pittsburgh, PA; Robert M. Berne Cardiovascular Research Center (J.T.B., M.B., S.M.M., T.J., A.K.B., B.E.I.), Department of Molecular Physiology and Biophysics (M.B., M.V.A., A.V.S., B.E.I.), Deparment of Pediatrics (L.A.P.), Department of Chemistry (L.C.), and Department of Medicine (T.H.L.), University of Virginia, Charlottesville. brant@virginia.edu.
University of Pittsburgh · US
Funding
BASIC CARDIOVASCULAR RESEARCH TRAINING GRANTT32HL007284 · NHLBI · UNIVERSITY OF VIRGINIA CHARLOTTESVILLE · PI Brant E Isakson, Gary K Owens · 1985 to 2026
$19.6MS-nitrosothiol signaling in pulmonary epithelial cellsP01HL101871 · NHLBI · UNIVERSITY OF VIRGINIA · PI GASTON, BENJAMIN, LEWIS, STEPHEN JOHN · 2011 to 2015
$8.7MMolecular Mechanisms of RhoA-mediated Ca2+Sensitization in Vascular Smooth MuscleR01GM086457 · NIGMS · UNIVERSITY OF VIRGINIA · PI DEREWENDA, URSZULA, DEREWENDA, ZYGMUNT S · 2009 to 2017
$5.4MAirway redox biochemistry as a deteriminant of asthma phenotype during adolescen*U10HL109250 · NHLBI · UNIVERSITY OF VIRGINIA · PI ERZURUM, SERPIL C., GASTON, BENJAMIN · 2011 to 2016
$4.2MMechanisms of Heterocellular Signaling at the Myoenothelial JunctionR01HL088554 · NHLBI · UNIVERSITY OF VIRGINIA · PI ISAKSON, BRANT E, WEISS, MITCHELL J · 2008 to 2017
$3.8MRenal and Epithelial Biology Training ProgramT32DK061296 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI KLEYMAN, THOMAS R · 2002 to 2022
$3.1MStructure and dynamics of bacterial membrane protein - receptor interactionsR01GM087828 · NIGMS · UNIVERSITY OF VIRGINIA · PI COLUMBUS, LINDA M · 2009 to 2018
$2.7MMyosin phosphatase autoinhibition in gastrointestinal smooth muscle contractionR01DK088905 · NIDDK · UNIVERSITY OF VIRGINIA · PI ETO, MASUMI, SOMLYO, AVRIL V. · 2010 to 2012
$1.1MMechanisms of Intracellular NAMPT-regulated GSNOR in Vessel WallR00HL112904 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI STRAUB, ADAM CARL · 2013 to 2015
$730kMechanism of PAI-1 Polarization to Myoendothelial JunctionsR21HL107963 · NHLBI · UNIVERSITY OF VIRGINIA · PI ISAKSON, BRANT E · 2012 to 2013
$414kMechanisms of intracellular NAMPT-regulated GSNOR in vessel wallK99HL112904 · NHLBI · UNIVERSITY OF VIRGINIA · PI STRAUB, ADAM CARL · 2012 to 2012
$90kNHLBI NIH HHS HL088554NHLBI NIH HHS HL107963NHLBI NIH HHS HL112904NHLBI NIH HHS K99 HL112904NHLBI NIH HHS P01 HL101871NHLBI NIH HHS R00 HL112904NHLBI NIH HHS R01 HL088554NHLBI NIH HHS R21 HL107963NHLBI NIH HHS T32 HL007284NHLBI NIH HHS U10 HL109250NIDDK NIH HHS DK06129611NIDDK NIH HHS DK088905NIDDK NIH HHS R01 DK088905NIDDK NIH HHS T32 DK061296NIGMS NIH HHS GM086457NIGMS NIH HHS GM087828NIGMS NIH HHS R01 GM086457NIGMS NIH HHS R01 GM087828
Abstract
objectiveHemoglobin 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
resultsIn 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.
conclusionsThese 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.
Indexed as
alpha-GlobinsAmino Acid SequenceAnimalsBlood PressureCells, CulturedComputer SimulationConserved SequenceEndothelial CellsHumansIntercellular JunctionsMaleMiceMice, Inbred C57BLMice, KnockoutModels, MolecularMolecular Sequence Dataalpha-GlobinsNitric OxideNitric Oxide Synthase Type IIINos3 protein, mouseRecombinant Proteinsendothelial cellsendothelial nitric oxide synthasehemoglobin αnitric oxide
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