Purinergic Signalling (2006) 2:471–480 DOI 10.1007/s11302-006-9015-1 P2 receptors in atherosclerosis and postangioplasty restenosis Cheikh I. Seye & Qiongman Kong & Ningpu Yu & Fernando A. Gonzalez & Laurie Erb & Gary A. Weisman Received: 9 January 2006 / Accepted: 8 May 2006 / Published online: 14 June 2006 # Springer Science + Business Media B.V. 2006 Abstract Atherosclerosis is an immunoinflammatory pro- cess that involves complex interactions between the vessel wall and blood components and is thought to be initiated by endothelial dysfunction [1–3]. Extracellular nucleotides that are released from a variety of arterial and blood cells [4] can bind to P2 receptors and modulate proliferation and migration of smooth muscle cells (SMC), which is known to be involved in intimal hyperplasia that accompanies atherosclerosis and postangioplasty restenosis [5]. In addition, P2 receptors mediate many other functions, including platelet aggregation, leukocyte adherence, and arterial vasomotoricity. A direct pathological role of P2 receptors is reinforced by recent evidence showing that up- regulation and activation of P2Y2 receptors in rabbit arteries mediates intimal hyperplasia [6]. In addition, up- regulation of functional P2Y receptors also has been demonstrated in the basilar artery of the rat double- hemorrhage model [7] and in coronary arteries of diabetic dyslipidemic pigs [8]. It has been proposed that up- regulation of P2Y receptors may be a potential diagnostic indicator for the early stages of atherosclerosis [9]. Therefore, particular effort must be made to understand the consequences of nucleotide release from cells in the cardiovascular system and the subsequent effects of P2 C. I. Seye (*) : Q. Kong : N. Yu : L. Erb : G. A. Weisman Department of Biochemistry, 540C Life Sciences Center, University of Missouri – Columbia, 1201 Rollins Road, Columbia, MO 65211-7310, USA e-mail: seyec@missouri.edu F. A. Gonzalez Department of Chemistry, Rio Piedras Campus, University of Puerto – Rico, San Juan, PR 00931, USA nucleotide receptor activation in blood vessels, which may reveal novel therapeutic strategies for atherosclerosis and restenosis after angioplasty. Key words atherosclerosis . inflammation . migration . nucleotide receptors . proliferation . restenosis . smooth muscle cell Introduction Atherosclerosis is a pathological phenomenon primarily affecting the large conduit arteries, for example, the aorta and coronary, carotid iliac, and femoral arteries. Develop- ment of atherosclerotic lesions in arteries involves intimal recruitment of smooth muscle cells (SMC) within the blood-vessel wall and also infiltration of blood-derived cells [1]. This process necessitates the proliferation and migration of SMC from the underlying media and the endothelial adhesion of leukocytes and their infiltration into the subendothelium. A similar intimal accumulation of SMC also takes place during the postangioplasty restenotic process. Although the factors involved in intimal-cell recruitment are not clearly identified, it is becoming evident that endothelial dysfunction is a key factor in the development of vascular disease. Experimental evidence suggests that an intact endothelium plays a central role in maintaining a low proliferative state of SMC under normal conditions [10]. In arterial injury, endothelial cells, SMC, and various blood cells can release chemotactic factors and mitogens, including ATP and other nucleotides [4]. Acti- vation of P2 nucleotide receptors has been shown to induce not only the proliferation and migration of vascular SMC but also apoptosis (programmed cell death), a process involved in the evolution of atherosclerotic plaque [11]. In