P2 receptors in atherosclerosis and postangioplasty restenosis

Abstract

Atherosclerosis is an immunoinflammatory process 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 nucleotide receptor activation in blood vessels, which may reveal novel therapeutic strategies for atherosclerosis and restenosis after angioplasty.

Purinergic Signaling and Blood Vessels in Health and Disease

“…ATP signaling is involved in atherosclerosis (Burnstock, 2002(Burnstock, , 2008bDi Virgilio and Solini, 2002;Plank et al, 2006Plank et al, , 2007Seye et al, 2006;Guns et al, 2010;Zerr et al, 2011). Adenosine and ATP promote endothelial and smooth muscle cell proliferation and increase expression of VEGF and growth of new vessels (Burnstock, 2002).…”

“…The long-term (trophic) roles of purinergic signaling in vascular smooth muscle and endothelial cell proliferation and death, which have been implicated in atherosclerosis and restenosis, suggest that therapeutic strategies in relation to these events should be explored (Di Virgilio and Solini, 2002;Ralevic and Burnstock, 2003;Seye et al, 2006;Burnstock, 2008b;Erlinge and Burnstock, 2008;Ralevic, 2009). …”

VAV2 regulates epidermal growth factor receptor endocytosis and degradation

“…Vav proteins associate with several receptor tyrosine kinases in addition to EGFR including platelet-derived growth factor, Eph, vascular endothelial growth factor and HGF receptors (Kodama et al, 2000;Pandey et al, 2000;Seye et al, 2004;Cowan et al, 2005;Gavard and Gutkind, 2006). Vav2 also associated with B-cell-specific CD19 and CD44v3 proteins (Doody et al, 2000;Bourguignon et al, 2001).…”

Extracellular Uridine Triphosphate and Adenosine Triphosphate Attenuate Endothelial Inflammation through miR-22-Mediated ICAM-1 Inhibition

“…A key step in the progression of atherosclerosis is the adhesion and transmigration of monocytes through the endothelial cells lining the vessel walls [3] . The nucleotides ATP and UTP are released into the extracellular space from vascular cells following a variety of stimuli related to atherosclerotic progression, such as ischemia, hypoxia and chemical and mechanical stress [4,5] . Extracellular nucleotides are known to have pleiotropic effects on the vascular wall, including vasodilation through the activation of endothelial nitric oxide synthase [6] , the release of proinflammatory cytokines [7] and the regulation of adhesion molecules such as VCAM-1 [8] .…”