Purinergic Signalling (2006) 2:471–480 vasoconstrictive substances, have previously been demon- strated [113, 114]. It appears that, like other receptors for vasoconstrictive factors such as angiotensin II [120], endothelin [121], and PDGF [122], which are overex- pressed in neointima, P2Y2 receptors may play an impor- tant role in controlling vasoactive properties of pathological arteries, particularly in chronic constriction at the lesion site that is postulated to be one of the processes leading to postangioplasty restenosis [5, 110]. Conclusion P2 receptor subtypes, including P2Y2, P2X1 and P2X4, appear to play a role in responses to endothelial injury that are thought to be key events in the initiation of atheroscle- rosis and restenosis after angioplasty. P2Y2R up-regulation and activation in endothelial cells and SMC promote leukocyte transmigration and intimal thickening in arteries of animal models of vascular injury, suggesting a possible regulatory role for this receptor in mechanisms leading to neointimal hyperplasia after angioplasty. Although there are no selective P2Y2 receptor antagonists yet available, recent progress in small interfering RNA (siRNA) technology has made it possible to design small RNA interference molecules that can selectively inhibit P2 receptor subtype expression. Such molecules can be efficiently delivered into the vessel wall using adenoviral vectors. In addition, P2 receptor transgenic mice (i.e., mice in which the relevant receptor subtype has been deleted or overexpressed) will be valuable tools to substantiate the role that nucleotides and P2 receptors play in the etiology of cardiovascular disease. Further delineation of signaling pathways involved in these P2 receptor-mediated processes may help limit or prevent vascular diseases such as atherosclerosis and restenosis after angioplasty. References 1. Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362(6423):801–809 2. Fuster V, Badimon L, Badimon JJ, Chesebro JH (1992) The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med 326(4):242–250 3. Davies MJ, Woolf N (1993) Atherosclerosis: what is it and why does it occur? Br Heart J 69(1):S3–S11 4. Di Virgilio F, Solini A (2002) P2 receptors: new potential players in atherosclerosis. Br J Pharmacol 135(4):831–842 5. Lafont A, Guzman LA, Whitlow PL, Goormastic M, Cornhill JF, Chisolm GM (1995) Restenosis after experimental angioplasty: intimal, medial, and adventitial changes associated with con- strictive remodeling. Circ Res 76(6):996–1002 6. Seye CI, Kong Q, Erb L, Garrad RC, Krugh B, Wang M, Turner JT, Sturek M, Gonzalez FA, Weisman GA (2002) Functional P2Y2 nucleotide receptors mediate uridine 5’-triphosphate- 477 induced intimal hyperplasia in collared rabbit carotid arteries. Circulation 106(21):2720 –2726 7. Carpenter RC, Miao L, Miyagi Y, Bengten E, Zhang JH (2001) Thesis Altered expression of P2 receptor mRNAs in the basilar artery in a rat double hemorrhage model. Stroke 32(2):516–522 8. Hill BJ, Wamhoff BR, Sturek M (2001) Functional nucleotide receptor expression and sarcoplasmic reticulum morphology in dedifferentiated porcine coronary smooth muscle cells. J Vasc Res 38(5):432– 443 9. Elmaleh DR, Narula J, Babich JW, Petrov A, Fischman AJ, Khaw BA, Rapaport E, Zamecnik PC (1998) Rapid noninvasive detection of experimental atherosclerotic lesions with novel 99mTc-labeled diadenosine tetraphosphates. Proc Natl Acad Sci USA 95(2):691– 695 10. Casscells W (1992) Migration of smooth muscle and endothelial cells. Critical events in restenosis. Circulation 86(3):723–729 11. Isner JM, Kearney M, Bortman S, Passeri J (1995) Apoptosis in human atherosclerosis and restenosis. Circulation 91(11): 2703–2711 12. North RA, Surprenant A (2000) Pharmacology of cloned P2X receptors. Ann Rev Pharmacol Toxicol 40:563 –580 13. Cooper DM, Rodbell M (1979) ADP is a potent inhibitor of human platelet plasma membrane adenylate cyclase. Nature 282 (5738):517–518 14. Communi D, Gonzales NS, Detheux M, Brezillon S, Lannoy V, Parmentier M, Boeynaems J-M (2001) Identification of a novel human ADP receptor coupled to G1. J Biol Chem 276(44): 41479–41485 15. Ralevic V, Burnstock G (1991) Roles of P2-receptors in the cardiovascular system. Circulation 84(1):1–14 16. Saiag B, Milon D, Shacoori V, Allain H, Rault B, van den Driessche J (1992) Newly evidenced pyrimidinoceptors and the P2X receptors are present on the vascular smooth muscle and respectively mediate the UTP- and ATP-induced contractions of the dog maxillary internal vein. Res Commun Chem Pathol Pharmacol 76(1):89 –94 17. von Kügelgen I, Starke K (1990) Evidence for two separate vasoconstriction-mediating nucleotide receptors, both distinct from the P2X-receptor, in rabbit basilar artery: a receptor for pyrimidine nucleotides and a receptor for purine nucleotides. Naunyn-Schmiedeberg’s Arch Pharmacol 341(6):538–546 18. Ralevic V, Burnstock G (1998) Receptors for purines and pyrimidine. Pharmacol Rev 50(3):413–492 19. Guns PJ, Van Assche T, Fransen P, Robaye B, Boeynaems JM, Bult H (2006) Endothelium-dependent relaxation evoked by ATP and UTP in the aorta of P2Y2-deficient mice. Br J Pharmacol 147(5):569–574 20. Seye CI, Gadeau AP, Daret D, Dupuch F, Alzieu P, Capron L, Desgranges C (1997) Overexpression of P2Y2 receptor in intimal lesions of the rat aorta. Arterioscler Thromb Vasc Biol 17(12): 3602–3610 21. Malam-Souley R, Seye CI, Gadeau AP, Loirand G, Pillois X, Campan M, Pacaud P, Desgranges, C (1996) Nucleotide receptor P2u partially mediates ATP-induced cell cycle progression of aortic smooth muscle cells. J Cell Physiol 166(1):57–65 22. Kumari R, Goh G, Ng LL, Boarder MR (2003) ATP and UTP responses of cultured rat aortic smooth muscle cells revisited: dominance of P2Y2 receptors. Br J Pharmacol 140(7): 1169–1176 23. Malmsjo M, Hou M, Pendergast W, Erlinge D, Edvinsson L (2003) The stable pyrimidines UDPβS and UTPγS discriminate between contractile cerebrovascular P2 receptors. Eur J Pharmacol 458(3):305–311 24. Malmsjo M, Hou M, Pendergast W, Erlinge D, Edvinsson L (2003) Potent P2Y6 receptor mediated contractions in human cerebral arteries. BMC Pharmacol 3:4