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P2Y4 nucleotide receptor: a novel actor in post-natal cardiac development

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Abstract

Communication between endothelial cells and cardiomyocytes is critical for cardiac development and regeneration. However the mechanisms involved in these endothelial-cardiomyocyte interactions remain poorly understood. Nucleotides are released within the heart, especially under ischemia or pressure overload. The function of P2Y nucleotide receptors in cardiac development has never been investigated. Here we show that adult P2Y4-null mice display microcardia. P2Y4 nucleotide receptor is expressed in cardiac endothelial cells but not in cardiomyocytes. Loss of P2Y4 in cardiac endothelial cells strongly inhibits their growth, migration and PDGF-B secretion in response to UTP. Proliferation of microvessels and cardiomyocytes is reduced in P2Y4-null hearts early after birth, resulting in reduced heart growth. Our study uncovers mouse P2Y4 receptor as an essential regulator of cardiac endothelial cell function, and illustrates the involvement of endothelial-cardiomyocyte interactions in post-natal heart development. We also detected P2Y4 expression in human cardiac microvessels. P2Y4 receptor could constitute a therapeutic target to regulate cardiac remodelling and post-ischemic revascularisation.

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Acknowledgments

We thank Larissa di Pietrantonio, Olivier Vosters, Dominique Fokan, Hrag Esfahani and Steven Droogmans for help and technical assistance. The authors are grateful to Dr Andreas Markl for invaluable assistance in telemetry and helpful discussion. This work was supported by an Action de Recherche Concertée of the Communauté Française de Belgique, an Interuniversity Attraction Pole grant from the Politique Scientifique Fédérale (IAP-P6/30), Prime Minister’s Office, Federal Service for Science, Technology and Culture, by grants of the Fonds de la Recherche Scientifique Médicale (F.R.S.M.), the Fonds d’Encouragement à la Recherche (F.E.R.), the Fonds Emile DEFAY, the Fonds de la Recherche Scientifique Médicale of Belgium, the Walloon Region (Programme d’Excellence CIBLES), and the LifeSciHealth programme of the European Community (grant LSHB-2003-503337). D. Communi and C. Dessy are Senior Research Associates of the Fonds National de la Recherche Scientifique (F.N.R.S.). M. Horckmans is supported by the Fonds National de la Recherche Scientifique/FRIA, Belgium. Philippe Unger has received a grant from the “Fonds pour la Chirurgie Cardiaque”, Elvira Leon-Gomez is supported by a grant of the F.S.R. (Fonds Spécial de Recherche) of the U.C.L. (Université catholique de Louvain). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Building C (5th floor), Campus Erasme, 808 Route de Lennik, 1070, Brussels, Belgium

    Michael Horckmans, Sophie Clouet, Jean-Marie Boeynaems & Didier Communi

  2. Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, 6041, Gosselies, Belgium

    Bernard Robaye & Dorothée Cammarata

  3. Unit of Pharmacology and Therapeutics, Université catholique de Louvain, UCL-FATH 5349, 1200, Brussels, Belgium

    Elvira Léon-Gόmez, Jean-Luc Balligand & Chantal Dessy

  4. Department Biologie et pharmacologie des plaquettes sanguines: hémostase, thrombose, transfusion, UMR_S949 INSERM-Université de Strasbourg, Etablissement Français du Sang-Alsace, 67081, Strasbourg, France

    Nicolas Lantz & Christian Gachet

  5. Department of Cardiology, Erasme Hospital, Université Libre de Bruxelles, 1070, Brussels, Belgium

    Philippe Unger

  6. Département Thrombose and Angiogenèse, Service de Pharmacologie, Sanofi-Aventis, 31300, Toulouse, France

    Frédérique Dol-Gleizes, Paul Schaeffer & Pierre Savi

  7. Department of Laboratory Medicine, Erasme Hospital, Université Libre de Bruxelles, 1070, Brussels, Belgium

    Jean-Marie Boeynaems

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  1. Michael Horckmans
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Horckmans, M., Robaye, B., Léon-Gόmez, E. et al. P2Y4 nucleotide receptor: a novel actor in post-natal cardiac development. Angiogenesis 15, 349–360 (2012). https://doi.org/10.1007/s10456-012-9265-1

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