title: New insights on pyrimidine signalling within the arterial vasculature - Different roles for P2Y2 and P2Y6 receptors in large and small coronary arteries of the mouse.
abstract: Extracellular pyrimidines activate P2Y receptors on both smooth muscle cells and endothelial cells, leading to vasoconstriction and relaxation respectively. The aim of this study was to utilize P2Y knock-out (KO) mice to determine which P2Y receptor subtype are responsible for the contraction and relaxation in the coronary circulation and to establish whether P2Y receptors have different functions along the mouse coronary vascular tree. We tested stable pyrimidine analogues on isolated coronary arteries from P2Y2 and P2Y6 receptor KO mice in a myograph setup. In larger diameter segments of the left descending coronary artery (LAD) (lumen diameter~150μm) P2Y6 is the predominant contractile receptor for both UTP (uridine triphosphate) and UDP (uridine diphosphate) induced contraction. In contrast, P2Y2 receptors mediate endothelial-dependent relaxation. However, in smaller diameter LAD segments (lumen diameter~50μm), the situation is opposite, with P2Y2 being the contractile receptor and P2Y6 functioning as a relaxant receptor along with P2Y2. Immunohistochemistry was used to confirm smooth muscle and endothelial localization of the receptors. In vivo measurements of blood pressure in WT mice revealed a biphasic response to the stable analogue UDPβS. Based on the changes in P2Y receptor functionality along the mouse coronary arterial vasculature, we propose that UTP can act as a vasodilator downstream of its release, after being degraded to UDP, without affecting the contractile pyrimidine receptors. We also propose a model, showing physiological relevance for the changes in purinergic receptor functionality along the mouse coronary vascular tree.
authors.affiliation: Department of Clinical Experimental Research, Glostrup Research Institute, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark. Electronic address: kristian.agmund.haanes@regionh.dk.
authors.forename: Kristian Agmund
authors.initials: KA
authors.lastname: Haanes
authors.affiliation: Department of Clinical Experimental Research, Glostrup Research Institute, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
authors.forename: Stine
authors.initials: S
authors.lastname: Spray
authors.affiliation: Research Center for Ageing and Osteoporosis, Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
authors.forename: Susanne
authors.initials: S
authors.lastname: Syberg
authors.affiliation: Research Center for Ageing and Osteoporosis, Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark; Institute of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Denmark.
authors.forename: Niklas Rye
authors.initials: NR
authors.lastname: Jørgensen
authors.affiliation: Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaye
authors.affiliation: Pôle des Laboratoires, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Boeynaems
authors.affiliation: Department of Clinical Experimental Research, Glostrup Research Institute, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Edvinsson
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels / Q000378:metabolism*; D004727:Endothelium / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D011743:Pyrimidines / Q000378:metabolism* / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D058473:Receptors, Purinergic P2Y2 / Q000235:genetics / Q000378:metabolism*; D014530:Uridine Diphosphate / Q000378:metabolism / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D011743:Pyrimidines; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate; C030986:pyrimidine
keywords: Coronary circulation; Knock-out mice; P2Y2; P2Y6; Purinergic receptors