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. (April 2016)

• Record Type: Journal Article
• Authors: Haanes, Kristian Agmund; Spray, Stine; Syberg, Susanne; Jørgensen, Niklas Rye; Robaye, Bernard; Boeynaems, Jean-Marie; Edvinsson, Lars
• Is Part Of: Journal of molecular and cellular cardiology. Volume 93(2016:Apr.)
• Page Start: 1
• Page End: 11
• Publication Date: 2016-04
• Subjects: Coronary circulation -- Knock-out mice -- Purinergic receptors -- P2Y2 -- P2Y6; ATP adenosine triphosphate -- ATPγS adenosine-5′-O-(3-thiotriphosphate) -- EC50 50% of the maximum response -- ENTPDase ectonucleoside triphosphate diphosphohydrolase -- ET-1 endothelin-1 -- Emax max contraction -- INS45973 P1-(inosine 5′-)P4-(uridine 5′-)tetraphosphate -- KO knock-out -- LAD left descending artery -- MABP mean arterial blood pressure -- NO nitric oxide -- PGF2α prostaglandin F2α -- PSS physiological saline solution -- Rmax max relaxation -- UDP uridine diphosphate -- UDPβS uridine-5′-O-(2-) -- UTP uridine triphosphate -- UTPγS uridine-5′-O-(3-thiotriphosphate) -- WT wild type; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2016.01.025
• Languages: English
• ISSNs: 0022-2828

Abstract

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 ~ 150 μm) 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 ~ 50 μm), 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. Highlights: Isolated P2Y2 and P2Y6 arteries from KO mice were analysed by myography. Large arteries: P2Y6 causes contraction for both UTP and UDP; P2Y2 causes relaxation. Smaller arteries: P2Y2 causes contraction and P2Y6 relaxation together with P2Y2. The receptor functionality appeared similar in systemic blood pressure measurements. P2Y receptor functionality changes along the coronary arterial vasculature.