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Nucleotides and Novel Signaling Pathways in Endothelial Cells: Possible Roles in Angiogenesis, Endothelial Dysfunction and Diabetes Mellitus

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Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function

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Abstract

In this chapter, we will focus on the signal transduction pathways in endothelial cells (ECs) studied by us and other groups. We will present data showing nucleotide-mediated activation of focal adhesion kinase (FAK), AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS), and document the role of Ca2+ in these pathways. Activation by extracellular nucleotides of mitogen-activated protein kinases (MAPK), such as extracellular signal-regulated kinase (ERK), p38, and JUN NH2-terminal kinase (JNK), phosphatidylinositol-3 kinase (PI3K), as well as the mammalian target of rapamycin (mTOR) pathway will be also discussed. Our data indicate that extracellular nucleotides activate FAK and eNOS, and modulate αv integrin expression, EC cytoskeletal rearrangements and migration, functions associated with angiogenesis. Activation of eNOS and AMPK suggests that nucleotides acting through P2 receptors may exert anti-inflammatory, anti-oxidative, pro-proliferative, and anti-apoptotic effects in the endothelium. Sustaining of eNOS activation in ECs exposed to high glucose concentrations supports our hypothesis that extracellular nucleotides play a protective role against endothelial dysfunction observed in diabetes. We have also evidence that purine nucleotides increase intracellular energy levels, possibly protecting ECs from stress-related loss of intracellular ATP. Numerous nucleotide-mediated effects on the endothelium remain to be elucidated.

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References

  1. Abedi H, Zachary I. (1997) Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells. J Biol Chem 272:15442–51.

    Article  CAS  PubMed  Google Scholar 

  2. Ahmad S, Ahmad A, Ghosh M, Leslie CC, White CW. (2004) Extracellular ATP-mediated signaling for survival in hyperoxia-induced oxidative stress. J Biol Chem 279:16317–25.

    Article  CAS  PubMed  Google Scholar 

  3. Ahmad S, Ahmad A, White CW. (2006) Purinergic signaling and kinase activation for survival in pulmonary oxidative stress and disease. Free Radic Biol Med 41:29–40.

    Article  CAS  PubMed  Google Scholar 

  4. Albert JL, Boyle JP, Roberts JA, Challiss RA, Gubby SE, Boarder MR. (1997) Regulation of brain capillary endothelial cells by P2Y receptors coupled to Ca2+, phospholipase C and mitogen-activated protein kinase. Br J Pharmacol 122:935–41.

    Article  CAS  PubMed  Google Scholar 

  5. Anter E, Thomas SR, Schulz E, Shapira OM, Vita JA, Keaney JF, Jr. (2004) Activation of endothelial nitric-oxide synthase by the p38 MAPK in response to black tea polyphenols. J Biol Chem 279:46637–43.

    Article  CAS  PubMed  Google Scholar 

  6. Atkinson L, Milligan CJ, Buckley NJ, Deuchars J. (2002) An ATP-gated ion channel at the cell nucleus. Nature 420:42.

    Article  CAS  PubMed  Google Scholar 

  7. Avraham HK, Lee TH, Koh Y, Kim TA, Jiang S, Sussman M, Samarel AM, Avraham S. (2003) Vascular endothelial growth factor regulates focal adhesion assembly in human brain microvascular endothelial cells through activation of the focal adhesion kinase and related adhesion focal tyrosine kinase. J Biol Chem 278:36661–8.

    Article  CAS  PubMed  Google Scholar 

  8. Bagchi S, Liao Z, Gonzalez FA, Chorna NE, Seye CI, Weisman GA, Erb L. (2005) The P2Y2 nucleotide receptor interacts with alphav integrins to activate Go and induce cell migration. J Biol Chem 280:39050–7.

    Article  CAS  PubMed  Google Scholar 

  9. Ballerini P, Di Iorio P, Ciccarelli R, Nargi E, D'Alimonte I, Traversa U, Rathbone MP, Caciagli F. (2002) Glial cells express multiple ATP binding cassette proteins which are involved in ATP release. Neuroreport 13:1789–92.

    Article  CAS  PubMed  Google Scholar 

  10. Bar I, Guns PJ, Metallo J, Cammarata D, Wilkin F, Boeynams JM, Bult H, Robaye B. (2008) Knockout mice reveal a role for P2Y6 receptor in macrophages, endothelial cells, and vascular smooth muscle cells. Mol Pharmacol 74:777–84.

    Article  CAS  PubMed  Google Scholar 

  11. Bodin P, Burnstock G. (2001) Evidence that release of adenosine triphosphate from endothelial cells during increased shear stress is vesicular. J Cardiovasc Pharmacol 38:900–8.

    Article  CAS  PubMed  Google Scholar 

  12. Bodor ET, Waldo GL, Blaesius R, Harden TK. (2004) Delineation of ligand binding and receptor signaling activities of purified P2Y receptors reconstituted with heterotrimeric G proteins. Purinergic Signal 1:43–9.

    Article  CAS  PubMed  Google Scholar 

  13. Brake AJ, Wagenbach MJ, Julius D. (1994) New structural motif for ligand-gated ion channels defined by an ionotropic ATP receptor. Nature 371:519–23.

    Article  CAS  PubMed  Google Scholar 

  14. Brown CA, Patel V, Wilkinson G, Boarder MR. (1996) P2 purinoceptor-stimulated conversion of arginine to citrulline in bovine endothelial cells is reduced by inhibition of protein kinase C. Biochem Pharmacol 52:1849–54.

    Article  CAS  PubMed  Google Scholar 

  15. Burnstock G. (2002) Purinergic signaling and vascular cell proliferation and death. Arterioscler Thromb Vasc Biol 22:364–73.

    Article  PubMed  CAS  Google Scholar 

  16. Burnstock G. (2006) Purinergic signalling. Br J Pharmacol 147(Suppl 1):S172–81.

    CAS  PubMed  Google Scholar 

  17. Burnstock G. (2007) Purine and pyrimidine receptors. Cell Mol Life Sci 64:1471–83.

    Article  CAS  PubMed  Google Scholar 

  18. Burnstock G, Kennedy C. (1985) Is there a basis for distinguishing two types of P2-purinoceptor? Gen Pharmacol 16:433–40.

    CAS  PubMed  Google Scholar 

  19. Buvinic S, Briones R, Huidobro-Toro JP. (2002) P2Y(1) and P2Y(2) receptors are coupled to the NO/cGMP pathway to vasodilate the rat arterial mesenteric bed. Br J Pharmacol 136:847–56.

    Article  CAS  PubMed  Google Scholar 

  20. Buvinic S, Poblete MI, Donoso MV, Delpiano AM, Briones R, Miranda R, Huidobro-Toro JP. (2006) P2Y1 and P2Y2 receptor distribution varies along the human placental vascular tree: role of nucleotides in vascular tone regulation. J Physiol 573:427–43.

    Article  CAS  PubMed  Google Scholar 

  21. Cacicedo JM, Yagihashi N, Keaney JF, Jr., Ruderman NB, Ido Y. (2004) AMPK inhibits fatty acid-induced increases in NF-kappaB transactivation in cultured human umbilical vein endothelial cells. Biochem Biophys Res Commun 324:1204–9.

    Article  CAS  PubMed  Google Scholar 

  22. Chiao CW, Tostes RC, Webb RC. (2008) P2X7 receptor activation amplifies lipopolysaccharide-induced vascular hyporeactivity via interleukin-1 beta release. J Pharmacol Exp Ther 326:864–70.

    Article  CAS  PubMed  Google Scholar 

  23. Chu S, Bohlen HG. (2004) High concentration of glucose inhibits glomerular endothelial eNOS through a PKC mechanism. Am J Physiol Renal Physiol 287:F384–92.

    Article  CAS  PubMed  Google Scholar 

  24. Communi D, Raspe E, Pirotton S, Boeynaems JM. (1995) Coexpression of P2Y and P2U receptors on aortic endothelial cells. Comparison of cell localization and signaling pathways. Circ Res 76:191–8.

    CAS  PubMed  Google Scholar 

  25. Connelly L, Palacios-Callender M, Ameixa C, Moncada S, Hobbs AJ. (2001) Biphasic regulation of NF-kappa B activity underlies the pro- and anti-inflammatory actions of nitric oxide. J Immunol 166:3873–81.

    CAS  PubMed  Google Scholar 

  26. Corton JM, Gillespie JG, Hardie DG. (1994) Role of the AMP-activated protein kinase in the cellular stress response. Curr Biol 4:315–24.

    Article  CAS  PubMed  Google Scholar 

  27. Cotran RS, Pober JS. (1989) Effects of cytokines on vascular endothelium: their role in vascular and immune injury. Kidney Int 35:969–75.

    Article  CAS  PubMed  Google Scholar 

  28. da Silva CG, Jarzyna R, Specht A, Kaczmarek E. (2006) Extracellular nucleotides and adenosine independently activate AMP-activated protein kinase in endothelial cells: involvement of P2 receptors and adenosine transporters. Circ Res 98:e39–e47.

    Article  PubMed  CAS  Google Scholar 

  29. da Silva CG, Specht A, Wegiel B, Ferran C, Kaczmarek E. (2009) Mechanism of purinergic activation of endothelial nitric oxide synthase in endothelial cells. Circulation 119:871–9.

    Article  PubMed  CAS  Google Scholar 

  30. Dagher Z, Ruderman N, Tornheim K, Ido Y. (1999) The effect of AMP-activated protein kinase and its activator AICAR on the metabolism of human umbilical vein endothelial cells. Biochem Biophys Res Commun 265:112–5.

    Article  CAS  PubMed  Google Scholar 

  31. Dagher Z, Ruderman N, Tornheim K, Ido Y. (2001) Acute regulation of fatty acid oxidation and amp-activated protein kinase in human umbilical vein endothelial cells. Circ Res 88:1276–82.

    Article  CAS  PubMed  Google Scholar 

  32. Daniel T, Carling D. (2002) Expression and regulation of the AMP-activated protein kinase-SNF1 (sucrose non-fermenting 1) kinase complexes in yeast and mammalian cells: studies using chimaeric catalytic subunits. Biochem J 365:629–38.

    CAS  PubMed  Google Scholar 

  33. Dawicki DD, Chatterjee D, Wyche J, Rounds S. (1997) Extracellular ATP and adenosine cause apoptosis of pulmonary artery endothelial cells. Am J Physiol 273:L485–94.

    CAS  PubMed  Google Scholar 

  34. De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA, Jr., Shin WS, Liao JK. (1995) Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 96:60–8.

    Article  PubMed  Google Scholar 

  35. Di T, Sullivan JA, Magness RR, Zhang L, Bird IM. (2001) Pregnancy-specific enhancement of agonist-stimulated ERK-1/2 signaling in uterine artery endothelial cells increases Ca(2+) sensitivity of endothelial nitric oxide synthase as well as cytosolic phospholipase A(2). Endocrinology 142:3014–26.

    Article  CAS  PubMed  Google Scholar 

  36. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. (1999) Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399:601–5.

    Article  CAS  PubMed  Google Scholar 

  37. Dolmetsch RE, Xu K, Lewis RS. (1998) Calcium oscillations increase the efficiency and specificity of gene expression [see comments]. Nature 392:933–6.

    Article  CAS  PubMed  Google Scholar 

  38. Du XL, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M. (2001) Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest 108:1341–8.

    CAS  PubMed  Google Scholar 

  39. Dubyak GR, el-Moatassim C. (1993) Signal transduction via P2-purinergic receptors for extracellular ATP and other nucleotides. Am J Physiol 265:C577–C606.

    CAS  PubMed  Google Scholar 

  40. Dudzinski DM, Michel T. (2007) Life history of eNOS: partners and pathways. Cardiovasc Res 75:247–60.

    Article  CAS  PubMed  Google Scholar 

  41. Dulak J, Jozkowicz A, Dembinska-Kiec A, Guevara I, Zdzienicka A, Zmudzinska-Grochot D, Florek I, Wojtowicz A, Szuba A, Cooke JP. (2000) Nitric oxide induces the synthesis of vascular endothelial growth factor by rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 20:659–66.

    CAS  PubMed  Google Scholar 

  42. el-Remessy AB, Bartoli M, Platt DH, Fulton D, Caldwell RB. (2005) Oxidative stress inactivates VEGF survival signaling in retinal endothelial cells via PI 3-kinase tyrosine nitration. J Cell Sci 118:243–52.

    Article  CAS  PubMed  Google Scholar 

  43. Erb L, Liu J, Ockerhausen J, Kong Q, Garrad RC, Griffin K, Neal C, Krugh B, Santiago-Perez LI, Gonzalez FA, Gresham HD, Turner JT, Weisman GA. (2001) An RGD sequence in the P2Y(2) receptor interacts with alpha(V)beta(3) integrins and is required for G(o)-mediated signal transduction. J Cell Biol 153:491–501.

    Article  CAS  PubMed  Google Scholar 

  44. Federici M, Menghini R, Mauriello A, Hribal ML, Ferrelli F, Lauro D, Sbraccia P, Spagnoli LG, Sesti G, Lauro R. (2002) Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylation modification of signaling proteins in human coronary endothelial cells. Circulation 106:466–72.

    Article  CAS  PubMed  Google Scholar 

  45. Fulton D, Gratton JP, Sessa WC. (2001) Post-translational control of endothelial nitric oxide synthase: why isn't calcium/calmodulin enough? J Pharmacol Exp Ther 299:818–24.

    CAS  PubMed  Google Scholar 

  46. Gerasimovskaya EV, Ahmad S, White CW, Jones PL, Carpenter TC, Stenmark KR. (2002) Extracellular ATP is an autocrine/paracrine regulator of hypoxia-induced adventitial fibroblast growth. Signaling through extracellular signal-regulated kinase-1/2 and the Egr-1 transcription factor. J Biol Chem 277:44638–50.

    Article  CAS  PubMed  Google Scholar 

  47. Gerasimovskaya EV, Woodward HN, Tucker DA, Stenmark KR. (2008) Extracellular ATP is a pro-angiogenic factor for pulmonary artery vasa vasorum endothelial cells. Angiogenesis 11:169–82.

    Article  CAS  PubMed  Google Scholar 

  48. Gomes P, Srinivas SP, Van Driessche W, Vereecke J, Himpens B. (2005) ATP release through connexin hemichannels in corneal endothelial cells. Invest Ophthalmol Vis Sci 46:1208–18.

    Article  PubMed  Google Scholar 

  49. Gomes P, Srinivas SP, Vereecke J, Himpens B. (2006) Gap junctional intercellular communication in bovine corneal endothelial cells. Exp Eye Res 83:1225–37.

    Article  CAS  PubMed  Google Scholar 

  50. Gordon EL, Pearson JD, Slakey LL. (1986) The hydrolysis of extracellular adenine nucleotides by cultured endothelial cells from pig aorta. Feed-forward inhibition of adenosine production at the cell surface. J Biol Chem 261:15496–507.

    CAS  PubMed  Google Scholar 

  51. Graham A, McLees A, Kennedy C, Gould GW, Plevin R. (1996) Stimulation by the nucleotides, ATP and UTP of mitogen-activated protein kinase in EAhy 926 endothelial cells. Br J Pharmacol 117:1341–7.

    CAS  PubMed  Google Scholar 

  52. Grimaldo S, Tian F, Li LY. (2009) Sensitization of endothelial cells to VEGI-induced apoptosis by inhibiting the NF-kappaB pathway. Apoptosis 14:788–95.

    Article  CAS  PubMed  Google Scholar 

  53. Guns PJ, Korda A, Crauwels HM, Van Assche T, Robaye B, Boeynaems JM, Bult H. (2005) Pharmacological characterization of nucleotide P2Y receptors on endothelial cells of the mouse aorta. Br J Pharmacol 146:288–95.

    Article  CAS  PubMed  Google Scholar 

  54. Hardie DG, Salt IP, Davies SP. (2000) Analysis of the role of the AMP-activated protein kinase in the response to cellular stress. Methods Mol Biol 99:63–74.

    CAS  PubMed  Google Scholar 

  55. Harrington LS, Evans RJ, Wray J, Norling L, Swales KE, Vial C, Ali F, Carrier MJ, Mitchell JA. (2007) Purinergic 2X1 receptors mediate endothelial dependent vasodilation to ATP. Mol Pharmacol 72:1132–6.

    Article  CAS  PubMed  Google Scholar 

  56. Harrington LS, Mitchell JA. (2004) Novel role for P2X receptor activation in endothelium-dependent vasodilation. Br J Pharmacol 143:611–7.

    Article  CAS  PubMed  Google Scholar 

  57. Harrington LS, Mitchell JA. (2005) P2X1 receptors and the endothelium. Mem Inst Oswaldo Cruz 100(Suppl 1):111–2.

    CAS  PubMed  Google Scholar 

  58. Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, Hardie DG. (1996) Characterization of the AMP-activated protein kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem 271:27879–87.

    Article  CAS  PubMed  Google Scholar 

  59. Hechler B, Freund M, Ravanat C, Magnenat S, Cazenave JP, Gachet C. (2008) Reduced atherosclerotic lesions in P2Y1/apolipoprotein E double-knockout mice: the contribution of non-hematopoietic-derived P2Y1 receptors. Circulation 118:754–63.

    Article  CAS  PubMed  Google Scholar 

  60. Hida A, Kawakami A, Miyashita T, Yamasaki S, Nakashima K, Tanaka F, Izumi Y, Tamai M, Huang M, Ida H, Nakamura H, Origuchi T, Ueki Y, Eguchi K. (2004) Nitric oxide acts on the mitochondria and protects human endothelial cells from apoptosis. J Lab Clin Med 144:148–55.

    Article  CAS  PubMed  Google Scholar 

  61. Ido Y, Carling D, Ruderman N. (2002) Hyperglycemia-induced apoptosis in human umbilical vein endothelial cells: inhibition by the AMP-activated protein kinase activation. Diabetes 51:159–67.

    Article  CAS  PubMed  Google Scholar 

  62. Kaczmarek E, Erb L, Koziak K, Jarzyna R, Wink MR, Guckelberger O, Blusztajn JK, Trinkaus-Randall V, Weisman GA, Robson SC. (2005) Modulation of endothelial cell migration by extracellular nucleotides: involvement of focal adhesion kinase and phosphatidylinositol 3-kinase-mediated pathways. Thromb Haemost 93:735–42.

    CAS  PubMed  Google Scholar 

  63. Kaczmarek E, Koziak K, Sevigny J, Siegel JB, Anrather J, Beaudoin AR, Bach FH, Robson SC. (1996) Identification and characterization of CD39/vascular ATP diphosphohydrolase. J Biol Chem 271:33116–22.

    Article  CAS  PubMed  Google Scholar 

  64. Kalinowski L, Dobrucki LW, Szczepanska-Konkel M, Jankowski M, Martyniec L, Angielski S, Malinski T. (2003) Third-generation beta-blockers stimulate nitric oxide release from endothelial cells through ATP efflux: a novel mechanism for antihypertensive action. Circulation 107:2747–52.

    Article  CAS  PubMed  Google Scholar 

  65. Knight GE, Oliver-Redgate R, Burnstock G. (2003) Unusual absence of endothelium-dependent or -independent vasodilatation to purines or pyrimidines in the rat renal artery. Kidney Int 64:1389–97.

    Article  CAS  PubMed  Google Scholar 

  66. Koszalka P, Ozuyaman B, Huo Y, Zernecke A, Flogel U, Braun N, Buchheiser A, Decking UK, Smith ML, Sevigny J, Gear A, Weber AA, Molojavyi A, Ding Z, Weber C, Ley K, Zimmermann H, Godecke A, Schrader J. (2004) Targeted disruption of cd73/ecto-5′-nucleotidase alters thromboregulation and augments vascular inflammatory response. Circ Res 95:814–21.

    Article  CAS  PubMed  Google Scholar 

  67. Kronenwett R, Graf T, Nedbal W, Weber M, Steidl U, Rohr UP, Mohler T, Haas R. (2002) Inhibition of angiogenesis in vitro by alphav integrin-directed antisense oligonucleotides. Cancer Gene Ther 9:587–96.

    Article  CAS  PubMed  Google Scholar 

  68. Laird SM, Graham A, Paul A, Gould GW, Kennedy C, Plevin R. (1998) Tumour necrosis factor stimulates stress-activated protein kinases and the inhibition of DNA synthesis in cultures of bovine aortic endothelial cells. Cell Signal 10:473–80.

    Article  CAS  PubMed  Google Scholar 

  69. Lasso de la Vega MC, Terradez P, Obrador E, Navarro J, Pellicer JA, Estrela JM. (1994) Inhibition of cancer growth and selective glutathione depletion in Ehrlich tumour cells in vivo by extracellular ATP. Biochem J 298 (Pt 1):99–105.

    Google Scholar 

  70. Lee M, Hwang JT, Lee HJ, Jung SN, Kang I, Chi SG, Kim SS, Ha J. (2003) AMP-activated protein kinase activity is critical for hypoxia-inducible factor-1 transcriptional activity and its target gene expression under hypoxic conditions in DU145 cells. J Biol Chem 278:39653–61.

    Article  CAS  PubMed  Google Scholar 

  71. Li W-H, Llopis J, Whitney M, Zlokarnik G, Tsien RY. (1998) Cell-permeant caged InsP3 ester shows that Ca2+ spike frequency can optimize gene expression [see comments]. Nature 392:936–41.

    Article  CAS  PubMed  Google Scholar 

  72. Liao Z, Seye CI, Weisman GA, Erb L. (2007) The P2Y2 nucleotide receptor requires interaction with alpha v integrins to access and activate G12. J Cell Sci 120:1654–62.

    Article  CAS  PubMed  Google Scholar 

  73. Liu HT, Toychiev AH, Takahashi N, Sabirov RZ, Okada Y. (2008) Maxi-anion channel as a candidate pathway for osmosensitive ATP release from mouse astrocytes in primary culture. Cell Res 18:558–65.

    Article  CAS  PubMed  Google Scholar 

  74. Loscalzo J, Welch G. (1995) Nitric oxide and its role in the cardiovascular system. Prog Cardiovasc Dis 38:87–104.

    Article  CAS  PubMed  Google Scholar 

  75. Mathie RT, Ralevic V, Alexander B, Burnstock G. (1991) Nitric oxide is the mediator of ATP-induced dilatation of the rabbit hepatic arterial vascular bed. Br J Pharmacol 103:1602–6.

    CAS  PubMed  Google Scholar 

  76. Matsubara M, Hayashi N, Jing T, Titani K. (2003) Regulation of endothelial nitric oxide synthase by protein kinase C. J Biochem (Tokyo) 133:773–81.

    CAS  Google Scholar 

  77. Menzies J, Paul A, Kennedy C. (2003) P2X7 subunit-like immunoreactivity in the nucleus of visceral smooth muscle cells of the guinea pig. Auton Neurosci 106:103–9.

    Article  CAS  PubMed  Google Scholar 

  78. Miao LY, Tang JP, Esposito DP, Zhang JH. (2001) Age-related changes in P2 receptor mRNA of rat cerebral arteries. Exp Gerontol 37:67–79.

    Article  CAS  PubMed  Google Scholar 

  79. Montiel M, de la Blanca EP, Jimenez E. (2006) P2Y receptors activate MAPK/ERK through a pathway involving PI3K/PDK1/PKC-zeta in human vein endothelial cells. Cell Physiol Biochem 18:123–34.

    Article  CAS  PubMed  Google Scholar 

  80. Moser TL, Kenan DJ, Ashley TA, Roy JA, Goodman MD, Misra UK, Cheek DJ, Pizzo SV. (2001) Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin. Proc Natl Acad Sci USA 98:6656–61.

    Article  CAS  PubMed  Google Scholar 

  81. Motley ED, Eguchi K, Patterson MM, Palmer PD, Suzuki H, Eguchi S. (2007) Mechanism of endothelial nitric oxide synthase phosphorylation and activation by thrombin. Hypertension 49:577–83.

    Article  CAS  PubMed  Google Scholar 

  82. Nagata D, Mogi M, Walsh K. (2003) AMP-activated protein kinase (AMPK) signaling in endothelial cells is essential for angiogenesis in response to hypoxic stress. J Biol Chem 278:31000–6.

    Article  CAS  PubMed  Google Scholar 

  83. Naumann N, Siratska O, Gahr M, Rosen-Wolff A. (2005) P-glycoprotein expression increases ATP release in respiratory cystic fibrosis cells. J Cyst Fibros 4:157–68.

    Article  CAS  PubMed  Google Scholar 

  84. Nebe B, Bohn W, Sanftleben H, Rychly J. (1996) Induction of a physical linkage between integrins and the cytoskeleton depends on intracellular calcium in an epithelial cell line. Exp Cell Res 229:100–10.

    Article  CAS  PubMed  Google Scholar 

  85. Partovian C, Zhuang Z, Moodie K, Lin M, Ouchi N, Sessa WC, Walsh K, Simons M. (2005) PKCalpha activates eNOS and increases arterial blood flow in vivo. Circ Res 97:482–7.

    Article  CAS  PubMed  Google Scholar 

  86. Patel V, Brown C, Goodwin A, Wilkie N, Boarder MR. (1996) Phosphorylation and activation of p42 and p44 mitogen-activated protein kinase are required for the P2 purinoceptor stimulation of endothelial prostacyclin production. Biochem J 320 (Pt 1):221–6.

    CAS  PubMed  Google Scholar 

  87. Paul A, Torrie LJ, McLaren GJ, Kennedy C, Gould GW, Plevin R. (2000) P2Y receptor-mediated inhibition of tumor necrosis factor alpha -stimulated stress-activated protein kinase activity in EAhy926 endothelial cells. J Biol Chem 275:13243–9.

    Article  CAS  PubMed  Google Scholar 

  88. Peng HB, Libby P, Liao JK. (1995) Induction and stabilization of I kappa B alpha by nitric oxide mediates inhibition of NF-kappa B. J Biol Chem 270:14214–9.

    Article  CAS  PubMed  Google Scholar 

  89. Praetorius HA, Leipziger J. (2009) ATP release from non-excitable cells. Purinergic Signal 5:433–46.

    Article  CAS  PubMed  Google Scholar 

  90. Ralevic V, Burnstock G. (1991) Roles of P2-purinoceptors in the cardiovascular system. Circulation 84:1–14.

    CAS  PubMed  Google Scholar 

  91. Ramirez AN, Kunze DL. (2002) P2X purinergic receptor channel expression and function in bovine aortic endothelium. Am J Physiol Heart Circ Physiol 282:H2106–16.

    CAS  PubMed  Google Scholar 

  92. Randriamboavonjy V, Fleming I. (2005) Endothelial nitric oxide synthase (eNOS) in platelets: how is it regulated and what is it doing there? Pharmacol Rep 57(Suppl):59–65.

    PubMed  Google Scholar 

  93. Ransford GA, Fregien N, Qiu F, Dahl G, Conner GE, Salathe M. (2009) Pannexin 1 Contributes to ATP Release in Airway Epithelia. Am J Respir Cell Mol Biol 41:523–34.

    Article  CAS  Google Scholar 

  94. Ray FR, Huang W, Slater M, Barden JA. (2002) Purinergic receptor distribution in endothelial cells in blood vessels: a basis for selection of coronary artery grafts. Atherosclerosis 162:55–61.

    Article  CAS  PubMed  Google Scholar 

  95. Richardson A, Parsons T. (1996) A mechanism for regulation of the adhesion-associated proteintyrosine kinase pp125FAK [published erratum appears in Nature 1996 Jun 27;381(6585):810]. Nature 380:538–40.

    Article  CAS  PubMed  Google Scholar 

  96. Romanov RA, Rogachevskaja OA, Khokhlov AA, Kolesnikov SS. (2008) Voltage dependence of ATP secretion in mammalian taste cells. J Gen Physiol 132:731–44.

    Article  CAS  PubMed  Google Scholar 

  97. Romer LH, McLean N, Turner CE, Burridge K. (1994) Tyrosine kinase activity, cytoskeletal organization, and motility in human vascular endothelial cells. Mol Biol Cell 5:349–61.

    CAS  PubMed  Google Scholar 

  98. Rounds S, Yee WL, Dawicki DD, Harrington E, Parks N, Cutaia MV. (1998) Mechanism of extracellular ATP- and adenosine-induced apoptosis of cultured pulmonary artery endothelial cells. Am J Physiol 275:L379–88.

    CAS  PubMed  Google Scholar 

  99. Rumjahn SM, Baldwin KA, Buxton IL. (2007) P2y receptor-mediated angiogenesis via vascular endothelial growth factor receptor 2 signaling. Proc West Pharmacol Soc 50:58–60.

    CAS  PubMed  Google Scholar 

  100. Rumjahn SM, Yokdang N, Baldwin KA, Thai J, Buxton IL. (2009) Purinergic regulation of vascular endothelial growth factor signaling in angiogenesis. Br J Cancer 100:1465–70.

    Article  CAS  PubMed  Google Scholar 

  101. Schenk U, Westendorf AM, Radaelli E, Casati A, Ferro M, Fumagalli M, Verderio C, Buer J, Scanziani E, Grassi F. (2008) Purinergic control of T cell activation by ATP released through pannexin-1 hemichannels. Sci Signal 1:ra6.

    Article  PubMed  Google Scholar 

  102. Schneider JC, El Kebir D, Chereau C, Lanone S, Huang XL, De Buys Roessingh AS, Mercier JC, Dall'Ava-Santucci J, Dinh-Xuan AT. (2003) Involvement of Ca2+/calmodulin-dependent protein kinase II in endothelial NO production and endothelium-dependent relaxation. Am J Physiol Heart Circ Physiol 284:H2311–9.

    CAS  PubMed  Google Scholar 

  103. Schock SC, Leblanc D, Hakim AM, Thompson CS. (2008) ATP release by way of connexin 36 hemichannels mediates ischemic tolerance in vitro. Biochem Biophys Res Commun 368:138–44.

    Article  CAS  PubMed  Google Scholar 

  104. Sessa WC. (2004) eNOS at a glance. J Cell Sci 117:2427–9.

    Article  CAS  PubMed  Google Scholar 

  105. Sessa WC. (2005) Regulation of endothelial derived nitric oxide in health and disease. Mem Inst Oswaldo Cruz 100(Suppl 1):15–8.

    CAS  PubMed  Google Scholar 

  106. Seye CI, Kong Q, Yu N, Gonzalez FA, Erb L, Weisman GA. (2007) P2 receptors in atherosclerosis and postangioplasty restenosis. Purinergic Signal 3:153–62.

    Article  CAS  PubMed  Google Scholar 

  107. Seye CI, Yu N, Gonzalez FA, Erb L, Weisman GA. (2004) The P2Y2 nucleotide receptor mediates vascular cell adhesion molecule-1 expression through interaction with VEGF receptor-2 (KDR/Flk-1). J Biol Chem 279:35679–86.

    Article  CAS  PubMed  Google Scholar 

  108. Shattil SJ, Haimovich B, Cunningham M, Lipfert L, Parsons JT, Ginsberg MH, Brugge JS. (1994) Tyrosine phosphorylation of pp125FAK in platelets requires coordinated signaling through integrin and agonist receptors. J Biol Chem 269:14738–45.

    CAS  PubMed  Google Scholar 

  109. Shen J, DiCorleto PE. (2008) ADP stimulates human endothelial cell migration via P2Y1 nucleotide receptor-mediated mitogen-activated protein kinase pathways. Circ Res 102:448–56.

    Article  CAS  PubMed  Google Scholar 

  110. Simon J, Filippov AK, Goransson S, Wong YH, Frelin C, Michel AD, Brown DA, Barnard EA. (2002) Characterization and channel coupling of the P2Y(12) nucleotide receptor of brain capillary endothelial cells. J Biol Chem 277:31390–400.

    Article  CAS  PubMed  Google Scholar 

  111. Soltoff SP. (1998) Related adhesion focal tyrosine kinase and the epidermal growth factor receptor mediate the stimulation of mitogen-activated protein kinase by the G-protein-coupled P2Y2 receptor. Phorbol ester or [Ca2+]i elevation can substitute for receptor activation. J Biol Chem 273:23110–7.

    Article  CAS  PubMed  Google Scholar 

  112. Soslau G, Silverberg M, Brodsky I, McCarty PP. (1997) ATP modification of serotonin-induced contraction of the rat pulmonary artery. Proc Soc Exp Biol Med 214:233–41.

    CAS  PubMed  Google Scholar 

  113. Stein SC, Woods A, Jones NA, Davison MD, Carling D. (2000) The regulation of AMP-activated protein kinase by phosphorylation. Biochem J 345(Pt 3):437–43.

    Article  CAS  PubMed  Google Scholar 

  114. Sugiyama T, Kawamura H, Yamanishi S, Kobayashi M, Katsumura K, Puro DG. (2005) Regulation of P2X7-induced pore formation and cell death in pericyte-containing retinal microvessels. Am J Physiol Cell Physiol 288:C568–76.

    Article  CAS  PubMed  Google Scholar 

  115. Tanaka N, Kawasaki K, Nejime N, Kubota Y, Nakamura K, Kunitomo M, Takahashi K, Hashimoto M, Shinozuka K. (2004) P2Y receptor-mediated Ca(2+) signaling increases human vascular endothelial cell permeability. J Pharmacol Sci 95:174–80.

    Article  CAS  PubMed  Google Scholar 

  116. Thors B, Halldorsson H, Thorgeirsson G. (2004) Thrombin and histamine stimulate endothelial nitric-oxide synthase phosphorylation at Ser1177 via an AMPK mediated pathway independent of PI3K-Akt. FEBS Lett 573:175–80.

    Article  CAS  PubMed  Google Scholar 

  117. Van Daele P, Van Coevorden A, Roger PP, Boeynaems JM. (1992) Effects of adenine nucleotides on the proliferation of aortic endothelial cells. Circ Res 70:82–90.

    PubMed  Google Scholar 

  118. Vincent AM, Russell JW, Low P, Feldman EL. (2004) Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev 25:612–28.

    Article  CAS  PubMed  Google Scholar 

  119. von Albertini M, Palmetshofer A, Kaczmarek E, Koziak K, Stroka D, Grey ST, Stuhlmeier KM, Robson SC. (1998) Extracellular ATP and ADP activate transcription factor NF-kappa B and induce endothelial cell apoptosis. Biochem Biophys Res Commun 248:822–9.

    Article  Google Scholar 

  120. Waldo GL, Harden TK. (2004) Agonist binding and Gq-stimulating activities of the purified human P2Y1 receptor. Mol Pharmacol 65:426–36.

    Article  CAS  PubMed  Google Scholar 

  121. Wang L, Karlsson L, Moses S, Hultgardh-Nilsson A, Andersson M, Borna C, Gudbjartsson T, Jern S, Erlinge D. (2002) P2 receptor expression profiles in human vascular smooth muscle and endothelial cells. J Cardiovasc Pharmacol 40:841–53.

    Article  CAS  PubMed  Google Scholar 

  122. Witters LA, Kemp BE, Means AR. (2006) Chutes and Ladders: the search for protein kinases that act on AMPK. Trends Biochem Sci 31:13–6.

    Article  CAS  PubMed  Google Scholar 

  123. Xiao D, Bird IM, Magness RR, Longo LD, Zhang L. (2001) Upregulation of eNOS in pregnant ovine uterine arteries by chronic hypoxia. Am J Physiol Heart Circ Physiol 280:H812–20.

    CAS  PubMed  Google Scholar 

  124. 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. (2006) Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice. Nat Med 12:133–7.

    Article  CAS  PubMed  Google Scholar 

  125. Yamamoto K, Sokabe T, Ohura N, Nakatsuka H, Kamiya A, Ando J. (2003) Endogenously released ATP mediates shear stress-induced Ca2+ influx into pulmonary artery endothelial cells. Am J Physiol Heart Circ Physiol 285:H793–803.

    CAS  PubMed  Google Scholar 

  126. Yegutkin GG. (2008) Nucleotide- and nucleoside-converting ectoenzymes: Important modulators of purinergic signalling cascade. Biochim Biophys Acta 1783:673–94.

    Article  CAS  PubMed  Google Scholar 

  127. Yegutkin GG, Henttinen T, Jalkanen S. (2001) Extracellular ATP formation on vascular endothelial cells is mediated by ecto-nucleotide kinase activities via phosphotransfer reactions. Faseb J 15:251–60.

    Article  CAS  PubMed  Google Scholar 

  128. Zheng J, Wen Y, Chen DB, Bird IM, Magness RR. (2005) Angiotensin II elevates nitric oxide synthase 3 expression and nitric oxide production via a mitogen-activated protein kinase cascade in ovine fetoplacental artery endothelial cells. Biol Reprod 72:1421–8.

    Article  CAS  PubMed  Google Scholar 

  129. Zimmermann H. (2000) Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedebergs Arch Pharmacol 362:299–309.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Published and unpublished data that were presented and discussed in this chapter, were obtained by Cleide da Silva, Katarzyna Koziak, Robert Jarzyna, Anke Specht, Anne Spristersbach, Eva Csizmadia, Maryse Picher, Veronica Klepeis, Vickery Trinkaus-Randall, Jan Krzysztof Blusztajn, Agnes Kittel, Laurie Erb, Gary Weisman, Marcia Wink, Olaf Guckelberger, Simon Robson, Barbara Wegiel and Christiane Ferran, whom I would like to thank.

This work was supported in part by the National Institutes of Health (HL66167) and the Juvenile Diabetes Research Foundation (5-2007-736).

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  1. Center for Vascular Biology Research, Surgery Department, Microvascular Surgery Division, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, MA, USA

    Elzbieta Kaczmarek

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  1. Dept. Pediatrics, Pediatric Clinical Services, University of Colorado, Denver, East 19th Avenue 12700, Aurora, 80045, USA

    Evgenia Gerasimovskaya

  2. Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline Ave. 99, Boston, 02215, USA

    Elzbieta Kaczmarek

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Kaczmarek, E. (2010). Nucleotides and Novel Signaling Pathways in Endothelial Cells: Possible Roles in Angiogenesis, Endothelial Dysfunction and Diabetes Mellitus. In: Gerasimovskaya, E., Kaczmarek, E. (eds) Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3435-9_2

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