P2 receptors in cardiovascular regulation and disease

Abstract

The role of ATP as an extracellular signalling molecule is now well established and evidence is accumulating that ATP and other nucleotides (ADP, UTP and UDP) play important roles in cardiovascular physiology and pathophysiology, acting via P2X (ion channel) and P2Y (G protein-coupled) receptors. In this article we consider the dual role of ATP in regulation of vascular tone, released as a cotransmitter from sympathetic nerves or released in the vascular lumen in response to changes in blood flow and hypoxia. Further, purinergic long-term trophic and inflammatory signalling is described in cell proliferation, differentiation, migration and death in angiogenesis, vascular remodelling, restenosis and atherosclerosis. The effects on haemostasis and cardiac regulation is reviewed. The involvement of ATP in vascular diseases such as thrombosis, hypertension and diabetes will also be discussed, as well as various heart conditions. The purinergic system may be of similar importance as the sympathetic and renin-angiotensin-aldosterone systems in cardiovascular regulation and pathophysiology. The extracellular nucleotides and their cardiovascular P2 receptors are now entering the phase of clinical development.

Fig. 1

P2 receptor-mediated regulation of the circulation. See text for details. Purines and pyrimidines are released on the luminal side from endothelial cells, platelets and red blood cells (RBC) in response to hypoxia, acidosis, adrenaline, shear stress and other stimuli. When the endothelial cell layer is intact, the response is vasodilatation by the endothelial release of nitric oxide (NO), endothelium-derived hyperpolarising factor (EDHF) and prostaglandins (Pgl). When the endothelium is damaged, platelets accumulate, release ATP and ADP and mediate vasoconstriction via P2 receptors on the vascular smooth muscle cell (VSMC). On the adventitial side sympathetic and sensory nerves mediate vasoconstriction. Extracellular nucleotides are rapidly degraded by NTPDase1 on endothelium reducing ATP to AMP, followed by conversion to adenosine by CD73 (not shown). In the subendothelium NTPDase2 is present, degrading ATP to ADP, maintaining the platelet activating and contractile effects. Ado adenosine, CGRP calcitonin gene-related peptide, SP substance P

Fig. 2

Functional roles of P2 receptors in the atherosclerotic inflammatory plaque and during restenosis. See text for details. Purines and pyrimidines acting on P2 receptors stimulate vascular inflammation both by actions on the endothelial cell (EC) and by effects on inflammatory cells. Furthermore, they stimulate vascular smooth muscle cell (VSCM) proliferation, the conversion to synthetic phenotype and production of matrix proteins. Mitogenic P2 receptors are upregulated by growth factors and cytokines. IL interleukin, MCP-1 monocyte chemoattractant protein-1, ICAM-1 intercellular adhesion molecule-1, TSP thrombospondin, IDO indoleamine 2,3-dioxygenase

Fig. 3

Functional roles of purines and pyrimidines acting on P2 receptors in the regulation of the heart. See text for details. a ATP, UTP and UDP exert inotropic effects on cardiomyocytes leading to increased cardiac output. b UTP and UDP stimulate hypertrophy of cardiomyocytes, while ATP can have apoptotic effects. c UTP protects against ischaemic injury and cardiomyocyte cell death. ATP-degrading enzymes preserve endothelial integrity and protect against allograft rejection. NTPDase nucleoside triphosphate diphosphohydrolase

Fig. 4

P2 receptor-mediated regulation of coagulation and platelet aggregation. See text for details. ADP is an important mediator and positive feedback mechanism for platelet aggregation. Activated platelets stimulate coagulation, i.e. formation of a fibrin network. In contrast, ATP, ADP and UTP release tissue plasminogen activator (t-PA) from endothelial cells, resulting in degradation of the fibrin network. At the same time plasminogen activator inhibitor (PAI-1) is also released from endothelial cells by ATP stimulation, in turn inhibiting t-PA. Thus, P2 receptors regulate several balancing factors in haemostasis. Ado adenosine