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Central Role of P2Y6 UDP Receptor in Arteriolar Myogenic Tone.

  • Kauffenstein G From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.). gilles.kauffenstein@gmail.com.
  • Tamareille S From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • Prunier F From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • Roy C From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • Ayer A From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • Toutain B From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • Billaud M From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • Isakson BE From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • Grimaud L From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • Loufrani L From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • Rousseau P From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • Abraham P From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • Procaccio V From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • Monyer H From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • de Wit C From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • Boeynaems JM From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • Robaye B From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • Kwak BR From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
  • Henrion D From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).
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  • 2016-06-04
Published in:
  • Arteriosclerosis, thrombosis, and vascular biology. - 2016
myocytes, smooth muscle
myogenic tone
myosin light chains
nucleotides
purinoceptor P2Y6
rhoA GTP-binding protein
Adenosine Triphosphatases
Animals
Arterioles
Blood Pressure
Calcium Signaling
Cells, Cultured
Connexin 43
Disease Models, Animal
Dose-Response Relationship, Drug
Genotype
Heart Failure
Hydrolysis
Mechanotransduction, Cellular
Mesentery
Mice, Knockout
Mitogen-Activated Protein Kinases
Muscle, Smooth, Vascular
Myocardial Infarction
Myocytes, Smooth Muscle
Myosin Light Chains
Phenotype
Phosphorylation
Purinergic P2X Receptor Agonists
Receptors, Purinergic P2
Receptors, Purinergic P2X7
Uridine Diphosphate
Vasoconstriction
Vasoconstrictor Agents
rho GTP-Binding Proteins
English OBJECTIVE
Myogenic tone (MT) of resistance arteries ensures autoregulation of blood flow in organs and relies on the intrinsic property of smooth muscle to contract in response to stretch. Nucleotides released by mechanical strain on cells are responsible for pleiotropic vascular effects, including vasoconstriction. Here, we evaluated the contribution of extracellular nucleotides to MT.


APPROACH AND RESULTS
We measured MT and the associated pathway in mouse mesenteric resistance arteries using arteriography for small arteries and molecular biology. Of the P2 receptors in mouse mesenteric resistance arteries, mRNA expression of P2X1 and P2Y6 was dominant. P2Y6 fully sustained UDP/UTP-induced contraction (abrogated in P2ry6(-/-) arteries). Preventing nucleotide hydrolysis with the ectonucleotidase inhibitor ARL67156 enhanced pressure-induced MT by 20%, whereas P2Y6 receptor blockade blunted MT in mouse mesenteric resistance arteries and human subcutaneous arteries. Despite normal hemodynamic parameters, P2ry6(-/-) mice were protected against MT elevation in myocardial infarction-induced heart failure. Although both P2Y6 and P2Y2 receptors contributed to calcium mobilization, P2Y6 activation was mandatory for RhoA-GTP binding, myosin light chain, P42-P44, and c-Jun N-terminal kinase phosphorylation in arterial smooth muscle cells. In accordance with the opening of a nucleotide conduit in pressurized arteries, MT was altered by hemichannel pharmacological inhibitors and impaired in Cx43(+/-) and P2rx7(-/-) mesenteric resistance arteries.


CONCLUSIONS
Signaling through P2 nucleotide receptors contributes to MT. This mechanism encompasses the release of nucleotides coupled to specific autocrine/paracrine activation of the uracil nucleotide P2Y6 receptor and may contribute to impaired tissue perfusion in cardiovascular diseases.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/76402
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