Endothelium-Derived Vasoconstriction by Purines and Pyrimidines
2008; Lippincott Williams & Wilkins; Volume: 103; Issue: 10 Linguagem: Inglês
10.1161/circresaha.108.187963
ISSN1524-4571
Autores Tópico(s)Neuroscience of respiration and sleep
ResumoHomeCirculation ResearchVol. 103, No. 10Endothelium-Derived Vasoconstriction by Purines and Pyrimidines Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBEndothelium-Derived Vasoconstriction by Purines and Pyrimidines Geoffrey Burnstock Geoffrey BurnstockGeoffrey Burnstock From the Autonomic Neuroscience Centre, Royal Free and University College Medical School, London, United Kingdom. Originally published7 Nov 2008https://doi.org/10.1161/CIRCRESAHA.108.187963Circulation Research. 2008;103:1056–1057The article by Tölle et al1 claims to show for the first time that adenosine 5′-tetraphosphate (AP4) is released on mechanical stimulation from human microvascular endothelial cells in the perfused rat kidney and, further, that AP4 is the most potent mediator of vascular smooth muscle constriction via P2X1 receptors or, indeed, via noradrenaline.It is well established that ATP and UTP released from endothelial cells in response to sheer stress produced by changes in blood flow act largely on P2Y receptor subtypes (but also some P2X receptor subtypes) on endothelial cells to release nitric oxide (NO), leading to vasodilatation (Figure).2–5 Endothelium-derived contracting factors have been identified, notably endothelin-1, prostaglandin H2, thromboxane A2, and superoxide anions.6,7 Tölle et al1 present compelling evidence for the release of AP4 from endothelial cells in response to mechanical stimulation, which then acts as a vasoconstrictor of the smooth muscle of microvessels in the kidney via P2X1 receptors. The presence of P2X1 receptors on vascular smooth muscle is well established, and they have been shown to respond to ATP released as a cotransmitter with noradrenaline from perivascular sympathetic vasoconstrictor nerves.8 However, P2X1 receptors have also been described on endothelial cells of human internal mammary and radial arteries and saphenous vein.9 Occupation of endothelial P2X1 receptors in rat mesenteric arteries resulted in a small vasoconstriction, followed by a profound and sustained endothelium-dependent vasodilatation, although not via NO.10 In P2X1 knockout mice, the vasoconstrictor response to ATP released by nerve stimulation is abolished.11 However, whether the constrictive responses to AP4 are also abolished in P2X1 knockout mice has not been examined, nor are there any studies of changes in P2X1 receptor-mediated endothelium-dependent vasodilatation. Presumably there are no P2X1 receptors on endothelial cells of the kidney microvessels; otherwise, there would be competing vasodilator effects of AP4. A study of the role of P2X1 receptors in renal microvascular autoregulatory behavior in response to increases in renal perfusion pressure suggested that ATP released from macula densa cells12 was mediated by P2X1 receptors and the reduction of the autoregulatory responses in P2X1 knockout mice supported this hypothesis.13Download figureDownload PowerPointFigure. Purines and pyrimidines control vascular tone through P2 receptors. ATP, along with noradrenaline and neuropeptide Y, released from perivascular sympathetic nerves bind the P2X1 receptors (as well as P2X2, P2X4, and P2Y2 receptors in some vessels) on smooth muscle, resulting in vasoconstriction. P1(A1) receptors on sympathetic nerves bind adenosine, which arises from enzymatic breakdown of ATP, to inhibit transmitter release, as do P2Y1 prejunctional receptors. During conditions of shear stress and hypoxia, endothelial cells release ATP and UTP, which bind P2Y1 (via ADP) and P2Y2 and, in some vessels, P2X1 and P2X4 receptors to trigger production of nitric oxide and subsequent vasodilation. ATP and ADP secreted by aggregating platelets also stimulate these receptors. It is claimed that AP4 and Up4A are released from endothelial cells under mechanical stress to produce vasoconstriction via muscle P2X1 receptors and in the case of Up4A probably also via P2Y2 and P2Y4 receptors. Modified and with permission of the Nature Publishing Group from Burnstock G. Vessel tone and remodeling. Nat Med. 2006;12:16–17.AP4 activates P2Y, as well as P2X receptors.14 The decreasing effect of AP4 on blood pressure is mediated by P2Y receptors on endothelial cells, but under certain conditions, such as hemorrhage, AP4 produces vasoconstriction via smooth muscle P2X receptors, where it was noted to be more potent than ATP.15In addition to AP4, uridine adenosine tetraphosphate (Up4A) was also identified as a highly potent purinergic endothelium-derived vasoconstrictor by this group.16 However, in their present article, the researchers show that AP4 is more potent than Up4A, being an active vasoconstrictor in nanomolar concentrations. It is puzzling why the actions of ATP released from endothelial cells in response to shear stress are directed largely to endothelial cell P2 receptors, leading to vasodilatation (rather than smooth muscle P2X1 receptors), whereas AP4 released from endothelial cells is claimed in this article to act on P2X1 receptors on smooth muscle, leading to vasoconstriction. This raises the question as to whether ATP is released into the lumen while AP4 and Up4A are released from the basolateral surface of the endothelial cells.It is possible that AP4 is released from perivascular nerves together with ATP; it has been shown to be a potent agonist on rat midbrain synaptic terminal P2 receptors.17 AP4 has also been shown to be stored in chromaffin granules and in platelets, where it can be released into the circulation, inhibiting the platelet aggregation induced by adenosine diphosphate18 and regulating blood pressure.19It is clear that purinergic signaling is a major mechanism involved in the regulation of vascular tone, but there is still much to be learned about the sites and mechanisms of release of purines from endothelial cells that mediate vasodilatation and vasoconstriction and the variations in purinergic pathways that exist between different vessels.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Sources of FundingThe author is a corecipient of a Wellcome Trust grant for "The Role of P2X7 Receptors in Inflammatory Cytokine Production," as well as a senior advisor to a Seventh Framework European Union Consortium grant for "Purinergic Signaling in Bone and Osteoporosis." The author is also holder of a Leverhulme Emeritus Fellowship.DisclosuresNone.FootnotesCorrespondence to Autonomic Neuroscience Centre, Royal Free and University College Medical School, Rowland Hill St, London, NW3 2PF, United Kingdom. E-mail [email protected] References 1 Tölle M, Jankowski V, Schuchardt M, Wiedon A, Huang T, Hub F, Kowalska J, Jemielity J, Guranowski A, Loddenkemper C, Zidek W, Jankowski J, van der Giet M. Adenosine 5′-tetraphosphate is a highly potent purinergic endothelium-derived vasoconstrictor. Circ Res. 2008; 103: 1100–1108.LinkGoogle Scholar2 Burnstock G. Purinergic signalling and vascular cell proliferation and death. Arterioscler Thromb Vasc Biol. 2002; 22: 364–373.CrossrefMedlineGoogle Scholar3 Burnstock G. Dual control of vascular tone and remodelling by ATP released from nerves and endothelial cells. Pharmacol Rep. 2008; 60: 12–20.MedlineGoogle Scholar4 Ramirez AN, Kunze DL. P2X purinergic receptor channel expression and function in bovine aortic endothelium. Am J Physiol Heart Circ Physiol. 2002; 282: H2106–H2116.CrossrefMedlineGoogle Scholar5 Yamamoto K, Sokabe T, Matsumoto T, Yoshimura K, Shibata M, Ohura N, Fukuda T, Sato T, Sekine K, Kato S, Isshiki M, Fujita T, Kobayashi M, Kawamura K, Masuda H, Kamiya A, Ando J. Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice. Nat Med. 2006; 12: 133–137.CrossrefMedlineGoogle Scholar6 Lüscher TF, Boulanger CM, Dohi Y, Yang ZH. Endothelium-derived contracting factors. Hypertension. 1992; 19: 117–130.LinkGoogle Scholar7 Vanhoutte PM, Feletou M, Taddei S. Endothelium-dependent contractions in hypertension. Br J Pharmacol. 2005; 144: 449–458.CrossrefMedlineGoogle Scholar8 Burnstock G. Noradrenaline and ATP: cotransmitters and neuromodulators. J Physiol Pharmacol. 1995; 46: 365–384.MedlineGoogle Scholar9 Ray FR, Huang W, Slater M, Barden JA. Purinergic receptor distribution in endothelial cells in blood vessels: a basis for selection of coronary artery grafts. Atherosclerosis. 2002; 162: 55–61.CrossrefMedlineGoogle Scholar10 Harrington LS, Mitchell JA. Novel role for P2X receptor activation in endothelium-dependent vasodilation. Br J Pharmacol. 2004; 143: 611–617.CrossrefMedlineGoogle Scholar11 Vial C, Evans RJ. P2X1 receptor-deficient mice establish the native P2X receptor and a P2Y6-like receptor in arteries. Mol Pharmacol. 2002; 62: 1438–1445.CrossrefMedlineGoogle Scholar12 Bell PD, Lapointe JY, Sabirov R, Hayashi S, Peti-Peterdi J, Manabe K, Kovacs G, Okada Y. Macula densa cell signaling involves ATP release through a maxi anion channel. Proc Natl Acad Sci U S A. 2003; 100: 4322–4327.CrossrefMedlineGoogle Scholar13 Inscho EW, Cook AK, Imig JD, Vial C, Evans RJ. Physiological role for P2X1 receptors in renal microvascular autoregulatory behavior. J Clin Invest. 2003; 112: 1895–1905.CrossrefMedlineGoogle Scholar14 Burnstock G, King BF. Numbering of cloned P2 purinoceptors. Drug Dev Res. 1996; 38: 67–71.CrossrefGoogle Scholar15 Lee JW, Kong ID, Park KS, Jeong SW. Effects of adenosine tetraphosphate (ATPP) on vascular tone in the isolated rat aorta. Yonsei Med J. 1995; 36: 487–496.CrossrefMedlineGoogle Scholar16 Jankowski J, Jankowski V, Seibt B, Henning L, Zidek W, Schlüter H. Identification of dinucleoside polyphosphates in adrenal glands. Biochem Biophys Res Commun. 2003; 304: 365–370.CrossrefMedlineGoogle Scholar17 Gómez-Villafuertes R, Gualix J, Miras-Portugal MT, Pintor J. Adenosine 5′-tetraphosphate (Ap4), a new agonist on rat midbrain synaptic terminal P2 receptors. Neuropharmacology. 2000; 39: 2381–2390.CrossrefMedlineGoogle Scholar18 Lee JW, Jeon SJ, Kong ID, Jeong SW. Identification of adenosine 5′-tetraphosphate in rabbit platelets and its metabolism in blood. Korean J Physiol. 1995; 29: 217–223.Google Scholar19 McLennan AG, ed. Ap4A and Other Dinucleoside Polyphosphates. Boca Raton, Fla: CRC Press; 1992.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Pradhan R and Dash A (2021) An Integrative Data Mining Approach to Identify Purinergic Signaling Genes and Associated Neurodegenerative Diseases 2021 12th International Conference on Computing Communication and Networking Technologies (ICCCNT), 10.1109/ICCCNT51525.2021.9579700, 978-1-7281-8595-8, (1-5) Bomfim G, Musial D, Miranda-Ferreira R, Nascimento S, Jurkiewicz A, Jurkiewicz N and de Moura R (2019) Antihypertensive effects of the Vitis vinifera grape skin (ACH09) extract consumption elicited by functional improvement of P1 (A1) and P2 (P2X1) purinergic receptors in diabetic and hypertensive rats, PharmaNutrition, 10.1016/j.phanu.2019.100146, 8, (100146), Online publication date: 1-Jun-2019. 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