Causing pain and disability as well as a 6-fold increased risk of developing potentially fatal cardiovascular disease, atherosclerosis affects 8% of 60-69 year olds. Atherosclerotic plaques form as fatty streaks which develop into atheromas. Further progression and destabilization results in plaque rupture and occlusive thrombosis. Thrombotic diseases including myocardial infarction, stroke, peripheral occlusive arterial disease and pulmonary embolism, affect almost 20 million people in the US alone resulting in close to 1 million deaths each year. Stroke and peripheral occlusive arterial disease also contribute strongly to permanent disability as a result of paralysis and limb loss. In addition to human cost economic costs are immense and consequently improved therapies able to prevent the progression of atherosclerosis are much in need. Receptors for extracellular nucleotides (P2 receptors) represent one focus of current pharmaceutical attention. Plaque progression involves a considerable immune component. All cells participating in the inflammatory response express at least one, but more often several, P2 subtypes, and furthermore stimulation of these receptors triggers or modulates key responses such as chemotaxis, cytokine secretion, NO release, platelet aggregation, proliferation, surface antigen shedding or cytotoxicity. Non-immune cells that participate in the formation of the atherosclerotic plaque (smooth muscle cells, fibroblasts, platelets, endothelial cells) also express P2 receptors and have an undisputed role in the modulation of vascular tone. The involvement of the purinergic system in atherosclerotic progression is not only suggested by receptor expression but also from the release of the principal ligands for these receptors, ATP and ADP into the plaque environment. Indeed, platelet aggregation, shear-stress and endothelial damage, all factors in atherosclerosis, release these purinergic mediators. Furthermore resulting activation of P2 receptors, drives smooth muscle cell migration and proliferation; monocyte/macrophage chemotaxis and release of IL-1B, TNFa and IL-18; secretion of IL-6 from fibroblasts; platelet aggregation and; cell death by necrosis or apoptosis. Each of these repsonses contributes to the progression of atherosclerosis. Thus, the proof of concept for the development of selective P2 antagonists is immense. Furthermore, clinical trials have shown the benefit of platelet ADP receptor antagonist in the prevention of vascular accidents in patients with atherosclerosis. Considering the multiple subtypes involved in the P2 receptor system, the opportunities for improved purinergic modulation in the field of cardiovascular disease is immense yet this area remains under exploited. It is therefore anticipated that a deeper understanding of the involvement of P2 receptors in atheroma formation will open new avenues for drug design and therapeutic intervention.

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