Molecular mechanisms underlying the activation of eNOS

Cardiovascular Physiology

Abstract

Endothelial cells situated at the interface between blood and the vessel wall play a crucial role in controlling vascular tone and homeostasis, particularly in determining the expression of pro- and anti-atherosclerotic genes. Many of these effects are mediated by changes in the generation and release of the vasodilator nitric oxide (NO) in response to hemodynamic stimuli exerted on the luminal surface of endothelial cells by the streaming blood (shear stress) and the cyclic strain of the vascular wall. The endothelial NO synthase (eNOS) is activated in response to fluid shear stress and numerous agonists via cellular events such as; increased intracellular Ca2+, interaction with substrate and co-factors, as well as adaptor and regulatory proteins, protein phosphorylation, and through shuttling between distinct sub-cellular domains. Dysregulation of these processes leads to attenuated eNOS activity and reduced NO output which is a characteristic feature of numerous patho-physiological disorders such as diabetes and atherosclerosis. This review summarizes some of the recent findings relating to the molecular events regulating eNOS activity.

Keywords

Endothelium Mechanoreceptor Nitric oxide synthase Oxidative stress Phosphorylation Shear stress 

References

  1. 1.
    Aicher A, Heeschen C, Mildner-Rihm C, Urbich C, Ihling C, Technau-Ihling K, Zeiher AM, Dimmeler S (2003) Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 9:1370–1376PubMedCrossRefGoogle Scholar
  2. 2.
    Andries LJ, Brutsaert DL, Sys SU (1998) Nonuniformity of endothelial constitutive nitric oxide synthase distribution in cardiac endothelium. Circ Res 82:195–203PubMedGoogle Scholar
  3. 3.
    Aoyagi M, Arvai AS, Tainer JA, Getzoff ED (2003) Structural basis for endothelial nitric oxide synthase binding to calmodulin. EMBO J 22:766–775PubMedCrossRefGoogle Scholar
  4. 4.
    Ayajiki K, Kindermann M, Hecker M, Fleming I, Busse R (1996) Intracellular pH and tyrosine phosphorylation but not calcium determine shear stress-induced nitric oxide production in native endothelial cells. Circ Res 78:750–758PubMedGoogle Scholar
  5. 5.
    Bagi Z, Frangos JA, Yeh JC, White CR, Kaley G, Koller A (2005) PECAM-1 mediates NO-dependent dilation of arterioles to high temporal gradients of shear stress. Arterioscler Thromb Vasc Biol 25:1590–1595PubMedCrossRefGoogle Scholar
  6. 6.
    Balligand JL, Feron O, Dessy C (2009) eNOS activation by physical forces: from short-term regulation of contraction to chronic remodeling of cardiovascular tissues. Physiol Rev 89:481–534PubMedCrossRefGoogle Scholar
  7. 7.
    Bauer PM, Fulton D, Boo YC, Sorescu GP, Kemp BE, Jo H, Sessa WC (2003) Compensatory phosphorylation and protein-protein interactions revealed by loss of function and gain of function mutants of multiple serine phosphorylation sites in endothelial nitric oxide synthase. J Biol Chem 278:14841–14849PubMedCrossRefGoogle Scholar
  8. 8.
    Bauersachs J, Widder JD (2008) Endothelial dysfunction in heart failure. Pharmacol Rep 60:119–126PubMedGoogle Scholar
  9. 9.
    Billecke SS, Bender AT, Kanelakis KC, Murphy PJ, Lowe ER, Kamada Y, Pratt WB, Osawa Y (2002) HSP90 is required for heme binding and activation of APO-neuronal nitric-oxide synthatse: geldanamycin-mediated oxidant generation is unrelated to any action of HSP90. J Biol Chem 277(23):20504–20509PubMedCrossRefGoogle Scholar
  10. 10.
    Black SM, Heidersbach RS, McMullan DM, Bekker JM, Johengen MJ, Fineman JR (1999) Inhaled nitric oxide inhibits NOS activity in lambs: potential mechanism for rebound pulmonary hypertension. Am J Physiol Heart Circ Physiol 277:H1849–H1856Google Scholar
  11. 11.
    Boo YC, Hwang J, Sykes M, Michell BJ, Kemp BE, Lum H, Jo H (2002) Shear stress stimulates phosphorylation of eNOS at Ser635 by a protein kinase A-dependent mechanism. Am J Physiol Heart Circ Physiol 283:H1819–H1828PubMedGoogle Scholar
  12. 12.
    Boo YC, Jo H (2003) Flow-dependent regulation of endothelial nitric oxide synthase: role of protein kinases. Am J Physiol Cell Physiol 285:C499–C508PubMedGoogle Scholar
  13. 13.
    Bredt DS, Snyder SH (1990) Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 87:682–685PubMedCrossRefGoogle Scholar
  14. 14.
    Bucci M, Gratton JP, Rudic RD, Acevedo L, Roviezzo F, Cirino G, Sessa WC (2000) In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation. Nat Med 6:1362–1367PubMedCrossRefGoogle Scholar
  15. 15.
    Busse R, Mülsch A (1990) Calcium-dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin. FEBS Lett 265:133–136PubMedCrossRefGoogle Scholar
  16. 16.
    Butt E, Bernhardt M, Smolenski A, Kotsonis P, Frohlich LG, Sickmann A, Meyer HE, Lohmann SM, Schmidt HHHW (2000) Endothelial nitric-oxide synthase (type III) is activated and becomes calcium independent upon phosphorylation by cyclic nucleotide-dependent protein kinases. J Biol Chem 275:5179–5187PubMedCrossRefGoogle Scholar
  17. 17.
    Cai H (2005) Hydrogen peroxide regulation of endothelial function: origins, mechanisms, and consequences. Cardiovasc Res 68:26–36PubMedCrossRefGoogle Scholar
  18. 18.
    Cao S, Yao J, Mccabe TJ, Yao Q, Katusic ZS, Sessa WC, Shah V (2001) Direct interaction between endothelial nitric-oxide synthase and dynamin-2. Implications for nitric-oxide synthase function. J Biol Chem 276:14249–14256PubMedGoogle Scholar
  19. 19.
    Cao S, Yao J, Shah V (2003) The proline-rich domain of dynamin-2 is responsible for dynamin- dependent in vitro potentiation of endothelial nitric-oxide synthase activity via selective effects on reductase domain function. J Biol Chem 278:5894–5901PubMedCrossRefGoogle Scholar
  20. 20.
    Chalupsky K, Cai H (2005) Endothelial dihydrofolate reductase: critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase. Proc Natl Acad Sci USA 102:9056–9061PubMedCrossRefGoogle Scholar
  21. 21.
    Channon K (2004) Tetrahydrobiopterin: regulator of endothelial nitric oxide synthase in vascular disease. Trends Cardiovasc Med 14:323–327PubMedCrossRefGoogle Scholar
  22. 22.
    Chatterjee S, Cao S, Peterson TE, Simari RD, Shah V (2003) Inhibition of GTP-dependent vesicle trafficking impairs internalization of plasmalemmal eNOS and cellular nitric oxide production. J Cell Sci 116:3645–3655PubMedCrossRefGoogle Scholar
  23. 23.
    Chauhan D, Pandey P, Hideshima T, Treon S, Raje N, Davies FE, Shima Y, Tai YT, Rosen S, Avraham S, Kharbanda S, Anderson KC (2000) SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells. J Biol Chem 275:27845–27850PubMedGoogle Scholar
  24. 24.
    Chen Z, Peng IC, Sun W, Su MI, Hsu PH, Fu Y, Zhu Y, DeFea K, Pan S, Tsai MD, Shyy JYJ (2009) AMP-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase Ser633. Circ Res 104:496–505PubMedCrossRefGoogle Scholar
  25. 25.
    Chiu YJ, Kusano K, Thomas TN, Fujiwara K (2004) Endothelial cell-cell adhesion and mechanosignal transduction. Endothelium 11:59–73PubMedCrossRefGoogle Scholar
  26. 26.
    Corson MA, James NL, Latta SE, Nerem RM, Berk BC, Harrison DG (1996) Phosphorylation of endothelial nitric oxide synthase in response to fluid shear stress. Circ Res 79:984–991PubMedGoogle Scholar
  27. 27.
    Crabtree MJ, Tatham AL, Hale AB, Alp NJ, Channon KM (2009) Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling. J Biol Chem 284:28128–28136PubMedCrossRefGoogle Scholar
  28. 28.
    Davda RK, Chandler LJ, Guzman NJ (1994) Protein kinase C modulates receptor-independent activation of endothelial nitric oxide synthase. Eur J Pharmacol 266:237–244PubMedCrossRefGoogle Scholar
  29. 29.
    Dayoub H, Achan V, Adimoolam S, Jacobi J, Stuehlinger MC, Wang By, Tsao PS, Kimoto M, Vallance P, Patterson AJ, Cooke JP (2003) Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation 108:3042–3047PubMedCrossRefGoogle Scholar
  30. 30.
    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 399:601–605PubMedCrossRefGoogle Scholar
  31. 31.
    Dixit M, Loot AE, Mohamed A, Fisslthaler B, Boulanger CM, Ceacareanu B, Hassid A, Busse R, Fleming I (2005) Gab1, SHP2, and protein kinase A are crucial for the activation of the endothelial NO synthase by fluid shear stress. Circ Res 97:1236–1244PubMedCrossRefGoogle Scholar
  32. 32.
    Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, Menne J, Lindschau C, Mende F, Luft FC, Schedl A, Haller H, Kurzchalia TV (2001) Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293:2449–2452PubMedCrossRefGoogle Scholar
  33. 33.
    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 108:1341–1348PubMedGoogle Scholar
  34. 34.
    Dunzendorfer S, Lee HK, Tobias PS (2004) Flow-dependent regulation of endothelial Toll-like receptor 2 expression through inhibition of SP1 activity. Circ Res 95:684–691PubMedCrossRefGoogle Scholar
  35. 35.
    Dusserre N, L'Heureux N, Bell KS, Stevens HY, Yeh J, Otte LA, Loufrani L, Frangos JA (2004) PECAM-1 interacts with nitric oxide synthase in human endothelial cells: implication for flow-induced nitric oxide synthase activation. Arterioscler Thromb Vasc Biol 24:1796–1802PubMedCrossRefGoogle Scholar
  36. 36.
    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 106:466–472PubMedCrossRefGoogle Scholar
  37. 37.
    Fisslthaler B, Dimmeler S, Hermann C, Busse R, Fleming I (2000) Phosphorylation and activation of the endothelial nitric oxide synthase by fluid shear stress. Acta Physiol Scand 168:81–88PubMedCrossRefGoogle Scholar
  38. 38.
    Fisslthaler B, Fleming I (2009) Activation and signaling by the AMP-activated protein kinase in endothelial cells. Circ Res 105:114–127PubMedCrossRefGoogle Scholar
  39. 39.
    Fisslthaler B, Loot AE, Mohamed A, Busse R, Fleming I (2008) Inhibition of endothelial nitric oxide synthase activity by proline-rich tyrosine kinase 2 in response to fluid shear stress and insulin. Circ Res 102:1520–1528PubMedCrossRefGoogle Scholar
  40. 40.
    Fleming I (2008) Biology of nitric oxide synthases. In: Tuma RF, Durán WN, Ley K (eds) Handbook of Physiology: Microcirculation 2. pp 56–80Google Scholar
  41. 41.
    Fleming I, Bauersachs J, Fisslthaler B, Busse R (1998) Ca2+-independent activation of the endothelial nitric oxide synthase in response to tyrosine phosphatase inhibitors and fluid shear stress. Circ Res 82:686–695PubMedGoogle Scholar
  42. 42.
    Fleming I, Fisslthaler B, Dimmeler S, Kemp BE, Busse R (2001) Phosphorylation of Thr495 regulates Ca2+/calmodulin-dependent endothelial nitric oxide synthase activity. Circ Res 88:e68–e75PubMedCrossRefGoogle Scholar
  43. 43.
    Fleming I, Fisslthaler B, Dixit M, Busse R (2005) Role of PECAM-1 in the shear-stress-induced activation of Akt and the endothelial nitric oxide synthase (eNOS) in endothelial cells. J Cell Sci 118:4103–4111PubMedCrossRefGoogle Scholar
  44. 44.
    Fleming I, Schulz C, Fichtlscherer B, Kemp BE, Fisslthaler B, Busse R (2003) AMP-activated protein kinase (AMPK) regulates the insulin-induced activation of the nitric oxide synthase in human platelets. Thromb Haemost 90:863–867PubMedGoogle Scholar
  45. 45.
    Fontana J, Fulton D, Chen Y, Fairchild TA, Mccabe TJ, Fujita N, Tsuruo T, Sessa WC (2002) Domain mapping studies reveal that the M domain of hsp90 serves as a molecular scaffold to regulate Akt-dependent phosphorylation of endothelial nitric oxide synthase and NO release. Circ Res 90:866–873PubMedCrossRefGoogle Scholar
  46. 46.
    Fulton D, Fontana J, Sowa G, Gratton JP, Lin M, Li KX, Michell B, Kemp BE, Rodman D, Sessa WC (2002) Localization of endothelial nitric-oxide synthase phosphorylated on serine 1179 and nitric oxide in Golgi and plasma membrane defines the existence of two pools of active enzyme. J Biol Chem 277:4277–4284PubMedCrossRefGoogle Scholar
  47. 47.
    Fulton D, Gratton J-P, Mccabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC (1999) Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399:597–601PubMedCrossRefGoogle Scholar
  48. 48.
    Fulton D, Church JE, Ruan L, Li C, Sood SG, Kemp BE, Jennings IG, Venema RC (2005) Src kinase activates endothelial nitric-oxide synthase by phosphorylating Tyr-83. J Biol Chem 280:35943–35952PubMedCrossRefGoogle Scholar
  49. 49.
    Fulton D, Ruan L, Sood SG, Li C, Zhang Q, Venema RC (2008) Agonist-stimulated endothelial nitric oxide synthase activation and vascular relaxation: role of eNOS phosphorylation at Tyr83. Circ Res 102:497–504PubMedCrossRefGoogle Scholar
  50. 50.
    Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376PubMedCrossRefGoogle Scholar
  51. 51.
    Gallis B, Corthals GL, Goodlett DR, Ueba H, Kim F, Presnell SR, Figeys D, Harrison DG, Berk BC, Aebersold R, Corson MA (1999) Identification of flow-dependent endothelial nitric oxide synthase phosphorylation sites by mass spectrometry and regulation of phosphorylation and nitric oxide production by the phosphatidylinositol 3-kinase inhibitor LY294002. J Biol Chem 274:30101–30108PubMedCrossRefGoogle Scholar
  52. 52.
    García-Cardena G, Fan G, Stern DF, Liu J, Sessa WC (1996) Endothelial nitric oxide synthase is regulated by tyrosine phosphorylation and interacts with caveolin-1. J Biol Chem 271:27237–27240PubMedCrossRefGoogle Scholar
  53. 53.
    García-Cardena G, Fan R, Shah V, Sorrentino R, Cirino G, Papapetropoulos A, Sessa WC (1998) Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature 292:821–824Google Scholar
  54. 54.
    García-Cardena G, Martasek P, Masters BS, Skidd PM, Couet J, Li S, Lisanti MP, Sessa WC (1997) Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the NOS caveolin binding domain in vivo. J Biol Chem 272:25437–25440PubMedCrossRefGoogle Scholar
  55. 55.
    García-Cardena G, Oh P, Liu J, Schnitzer JE, Sessa WC (1996) Targeting of nitric oxide synthase to endothelial cell caveolae via palmitoylation: implications for nitric oxide signaling. Proc Natl Acad Sci U S A 93:6448–6453PubMedCrossRefGoogle Scholar
  56. 56.
    Garcin ED, Bruns CM, Lloyd SJ, Hosfield DJ, Tiso M, Gachhui R, Stuehr DJ, Tainer JA, Getzoff ED (2004) Structural basis for isozyme-specific regulation of electron transfer in nitric-oxide synthase. J Biol Chem 279:37918–37927PubMedCrossRefGoogle Scholar
  57. 57.
    Ghosh S, Gachhui R, Crooks C, Wu CQ, Lisanti MP, Stuehr DJ (1998) Interaction between caveolin-1 and the reductase domain of endothelial nitric-oxide synthase—consequences for catalysis. J Biol Chem 273:22267–22271PubMedCrossRefGoogle Scholar
  58. 58.
    Gonzalez-Fernandez F, Jimenez A, Lopez-Blaya A, Velasco S, Arriero MM, Celdran A, Rico L, Farre J, Casado S, Lopez-Farre A (2001) Cerivastatin prevents tumor necrosis factor-alpha-induced downregulation of endothelial nitric oxide synthase: role of endothelial cytosolic proteins. Atherosclerosis 155:61–70PubMedCrossRefGoogle Scholar
  59. 59.
    Govers R, Bevers L, de Bree P, Rabelink TJ (2002) Endothelial nitric oxide synthase activity is linked to its presence at cell-cell contacts. Biochem J 361:193–201PubMedCrossRefGoogle Scholar
  60. 60.
    Gratton J-P, Fontana J, O'Connor DS, García-Cardena G, Mccabe TJ, Sessa WC (2000) Reconstitution of an endothelial nitric oxide synthase, hsp90 and caveolin-1 complex in vitro: evidence that hsp90 facilitates calmodulin stimulated displacement of eNOS from caveolin-1. J Biol Chem 275:22268–22272PubMedCrossRefGoogle Scholar
  61. 61.
    Gu H, Neel BG (2003) The "Gab" in signal transduction. Trends Cell Biol 13:122–130PubMedCrossRefGoogle Scholar
  62. 62.
    Harris MB, Ju H, Venema VJ, Liang H, Zou R, Michell BJ, Chen Z-P, Kemp BE, Venema RC (2001) Reciprocal phosphorylation and regulation of the endothelial nitric oxide synthase in response to bradykinin stimulation. J Biol Chem 19:16587–16591CrossRefGoogle Scholar
  63. 63.
    Jayachandran M, Hayashi T, Sumi D, Iguchi A, Miller VM (2001) Temporal effects of 17beta-estradiol on caveolin-1 mRNA and protein in bovine aortic endothelial cells. Am J Physiol Heart Circ Physiol 281:H1327–H1333PubMedGoogle Scholar
  64. 64.
    Jin ZG, Wong C, Wu J, Berk BC (2005) Flow shear stress stimulates Gab1 tyrosine phosphorylation to mediate protein kinase B and endothelial nitric oxide synthase activation in endothelial cells. J Biol Chem 280:12305–12309PubMedCrossRefGoogle Scholar
  65. 65.
    Ju H, Zou R, Venema VJ, Venema RC (1997) Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity. J Biol Chem 272:18522–18525PubMedCrossRefGoogle Scholar
  66. 66.
    Kou R, Prabhakar P, Michel T (2001) Phosphorylation of the endothelial isoform of nitric oxide synthase at serine 116: identification of a novel path for eNOS regulation by lysophosphatidic acid. Circulation 104:509Google Scholar
  67. 67.
    Kumar S, Sun X, Sharma S, Aggarwal S, Ravi K, Fineman JR, Black SM (2009) GTP cyclohydrolase I expression is regulated by nitric oxide: role of cyclic AMP. Am J Physiol Lung Cell Mol Physiol 297:L309–L317PubMedCrossRefGoogle Scholar
  68. 68.
    Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE, Harrison DG (2003) Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 111:1201–1209PubMedGoogle Scholar
  69. 69.
    Leiper J, Nandi M, Torondel B, Murray-Rust J, Malaki M, O'Hara B, Rossiter S, Anthony S, Madhani M, Selwood D, Smith C, Wojciak-Stothard B, Rudiger A, Stidwill R, McDonald NQ, Vallance P (2007) Disruption of methylarginine metabolism impairs vascular homeostasis. Nat Med 13:198–203PubMedCrossRefGoogle Scholar
  70. 70.
    Lev S, Moreno H, Martinez R, Canoll P, Peles E, Musacchio J, Plowman G, Rudy B, Schlessinger J (1995) Protein tyrosine kinase PYK2 involved in Ca2+-induced regulation of ion channel and MAP kinase functions. Nature 376:737–745PubMedCrossRefGoogle Scholar
  71. 71.
    Lin MI, Fulton D, Babbitt R, Fleming I, Busse R, Pritchard KA Jr, Sessa WC (2003) Phosphorylation of threonine 497 in endothelial nitric-oxide synthase coordinates the coupling of l-arginine metabolism to efficient nitric oxide production. J Biol Chem 278:44719–44726PubMedCrossRefGoogle Scholar
  72. 72.
    Loot AE, Schreiber J, Fisslthaler B, Fleming I (2009) Angiotensin II impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase. J Exp Med (in press)Google Scholar
  73. 73.
    Maniatis NA, Brovkovych V, Allen SE, John TA, Shajahan AN, Tiruppathi C, Vogel SM, Skidgel RA, Malik AB, Minshall RD (2006) Novel mechanism of endothelial nitric oxide synthase activation mediated by caveolae internalization in endothelial cells. Circ Res 99:870–877PubMedCrossRefGoogle Scholar
  74. 74.
    Matsubara M, Titani K, Taniguchi H (1996) Interaction of calmodulin-binding domain peptides of nitric oxide synthase with membrane phospholipids: regulation by protein phosphorylation and Ca2+-calmodulin. Biochemistry 35:14651–14658PubMedCrossRefGoogle Scholar
  75. 75.
    Michel JB, Feron O, Sacks D, Michel T (1997) Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin. J Biol Chem 272:15583–15586PubMedCrossRefGoogle Scholar
  76. 76.
    Michel T, Li GK, Busconi L (1993) Phosphorylation and subcellular translocation of endothelial nitric oxide synthase. Proc Natl Acad Sci USA 90:6252–6256PubMedCrossRefGoogle Scholar
  77. 77.
    Michell BJ, Chen Z, Tiganis T, Stapleton D, Katsis F, Power DA, Sim AT, Kemp BE (2001) Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase. J Biol Chem 276:17625–17628PubMedCrossRefGoogle Scholar
  78. 78.
    Michell BJ, Harris MB, Chen Z, Ju H, Venema VJ, Blackstone MA, Huang W, Venema RC, Kemp BE (2002) Identification of regulatory sites of phosphorylation of the bovine endothelial nitric-oxide synthase at serine 617 and serine 635. J Biol Chem 277:42344PubMedCrossRefGoogle Scholar
  79. 79.
    Monterio de Resende M, Huw L-Y, Qian H-S, Kauser K (2007) Role of endothelial nitric oxide in bone marrow-derived progenitor cell mobilization. Handb Exp Pharmacol 180:37–44PubMedCrossRefGoogle Scholar
  80. 80.
    Morris SM Jr (2009) Recent advances in arginine metabolism: roles and regulation of the arginases. Br J Pharmacol 157:922–930PubMedCrossRefGoogle Scholar
  81. 81.
    Newman PJ (1999) Switched at birth: a new family for PECAM-1. J Clin Invest 103:5–9PubMedCrossRefGoogle Scholar
  82. 82.
    Okuda M, Takahashi M, Suero J, Murry CE, Traub O, Kawakatsu H, Berk BC (1999) Shear stress stimulation of p130(cas) tyrosine phosphorylation requires calcium-dependent c-Src activation. J Biol Chem 274:26803–26809PubMedCrossRefGoogle Scholar
  83. 83.
    Orr AW, Murphy-Ullrich JE (2004) Regulation of endothelial cell function by FAK and PYK2. Front Biosci 9:1254–1266PubMedCrossRefGoogle Scholar
  84. 84.
    Osawa M, Masuda M, Kusano K, Fujiwara K (2002) Evidence for a role of platelet endothelial cell adhesion molecule-1 in endothelial cell mechanosignal transduction: is it a mechanoresponsive molecule? J Cell Biol 158:773–785PubMedCrossRefGoogle Scholar
  85. 85.
    Oubaha M, Gratton JP (2009) Phosphorylation of endothelial nitric oxide synthase by atypical PKCζ contributes to angiopoietin-1-dependent inhibition of VEGF-induced endothelial permeability in vitro. Blood 114:3343–3351PubMedCrossRefGoogle Scholar
  86. 86.
    Palmer RMJ, Ferridge AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526PubMedCrossRefGoogle Scholar
  87. 87.
    Pelligrino DA, Ye S, Tan F, Santizo RA, Feinstein DL, Wang Q (2000) Nitric-oxide-dependent pial arteriolar dilation in the female rat: effects of chronic estrogen depletion and repletion. Biochem Biophys Res Commun 269:165–171PubMedCrossRefGoogle Scholar
  88. 88.
    Pope AJ, Karuppiah K, Kearns PN, Xia Y, Cardounel AJ (2009) Role of dimethylarginine dimethylaminohydrolases in the regulation of endothelial nitric oxide production. J Biol Chem. doi:10.1074/jbc.M109.037036 Google Scholar
  89. 89.
    Pritchard KA Jr, Ackerman AW, Gross ER, Stepp DW, Shi Y, Fontana JT, Baker JE, Sessa WC (2001) Heat shock protein 90 mediates the balance of nitric oxide and superoxide anion from endothelial nitric-oxide synthase. J Biol Chem 276:17621–17624PubMedCrossRefGoogle Scholar
  90. 90.
    Randriamboavonjy V, Schrader J, Busse R, Fleming I (2004) Insulin induces the release of vasodilator compounds from platelets by a nitric oxide-G kinase-VAMP-3-dependent pathway. J Exp Med 199:347–356PubMedCrossRefGoogle Scholar
  91. 91.
    Razani B, Engelman JA, Wang XB, Schubert W, Zhang XL, Marks CB, Macaluso F, Russell RG, Li M, Pestell RG, Di Vizio D, Hou H Jr, Kneitz B, Lagaud G, Christ GJ, Edelmann W, Lisanti MP (2001) Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities. J Biol Chem 276:38121–38138PubMedCrossRefGoogle Scholar
  92. 92.
    Retzlaff M, Stahl M, Eberl HC, Lagleder S, Beck J, Kessler H, Buchner J (2009) Hsp90 is regulated by a switch point in the C-terminal domain. EMBO Rep 10:1147–1153PubMedCrossRefGoogle Scholar
  93. 93.
    Schmidt K, Rehn M, Stessel H, Wolkart G, Mayer B (2009) Evidence against tetrahydrobiopterin depletion of vascular tissue exposed to nitric oxide/superoxide or nitroglycerin. Free Radic Biol Med. doi:10.1016/j.freeradbiomed.2009.10.038
  94. 94.
    Schneider JC, El Kebir D, Chereau C, Lanone S, Huang XL, 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–H2319PubMedGoogle Scholar
  95. 95.
    Schulz E, Anter E, Zou MH, Keaney JF Jr (2005) Estradiol-mediated endothelial nitric oxide synthase association with heat shock protein 90 requires adenosine monophosphate-dependent protein kinase. Circulation 111:3473–3480PubMedCrossRefGoogle Scholar
  96. 96.
    Schulz E, Dopheide J, Schuhmacher S, Thomas SR, Chen K, Daiber A, Wenzel P, Munzel T, Keaney JF Jr (2008) Suppression of the JNK pathway by induction of a metabolic stress response prevents vascular injury and dysfunction. Circulation 118:1347–1357PubMedGoogle Scholar
  97. 97.
    Segal MS, Shah R, Afzal A, Perrault CM, Chang K, Schuler A, Beem E, Shaw LC, Li Calzi S, Harrison JK, Tran-Son-Tay R, Grant MB (2006) Nitric oxide cytoskeletal-induced alterations reverse the endothelial progenitor cell migratory defect associated with diabetes. Diabetes 55:102–109PubMedCrossRefGoogle Scholar
  98. 98.
    Segal SS, Brett SE, Sessa WC (1999) Codistribution of NOS and caveolin throughout peripheral vasculature and skeletal muscle of hamsters. Am J Physiol Heart Circ Physiol 277:H1167–H1177Google Scholar
  99. 99.
    Sessa WC, García-Cardena G, Liu J, Keh A, Pollock JS, Bradley J, Thiru S, Braverman IM, Desai KM (1995) The Golgi association of endothelial nitric oxide synthase is necessary for the efficient synthesis of nitric oxide. J Biol Chem 270:17641–17644PubMedCrossRefGoogle Scholar
  100. 100.
    Sugiyama T, Levy BD, Michel T (2009) Tetrahydrobiopterin recycling, a key determinant of endothelial nitric-oxide synthase-dependent signaling pathways in cultured vascular endothelial cells. J Biol Chem 284:12691–12700PubMedCrossRefGoogle Scholar
  101. 101.
    Tai LK, Okuda M, Abe J, Yan C, Berk BC (2002) Fluid shear stress activates proline-rich tyrosine kinase via reactive oxygen species-dependent pathway. Arterioscler Thromb Vasc Biol 22:1790–1796PubMedCrossRefGoogle Scholar
  102. 102.
    Takenouchi Y, Oo ML, Senga T, Watanabe Y, Machida K, Miyazaki K, Nimura Y, Hamaguchi M (2004) Tyrosine phosphorylation of NOS3 in a breast cancer cell line and Src-transformed cells. Oncol Rep 11:1059–1062PubMedGoogle Scholar
  103. 103.
    Tang H, Hao Q, Rutherford SA, Low B, Zhao ZJ (2005) Inactivation of Src family tyrosine kinases by reactive oxygen species in vivo. J Biol Chem 280:23918–23925PubMedCrossRefGoogle Scholar
  104. 104.
    Thomson MJ, Puntmann V, Kaski JC (2007) Atherosclerosis and oxidant stress: the end of the road for antioxidant vitamin treatment? Cardiovasc Drugs Ther 21:195–210PubMedCrossRefGoogle Scholar
  105. 105.
    Turi A, Kiss AL, Mullner N (2001) Estrogen downregulates the number of caveolae and the level of caveolin in uterine smooth muscle. Cell Biol Int 25:785–794PubMedCrossRefGoogle Scholar
  106. 106.
    Tzima E, Irani-Tehrani M, Kiosses WB, Dejana E, Schultz DA, Engelhardt B, Cao G, DeLisser H, Schwartz MA (2005) A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437:426–431PubMedCrossRefGoogle Scholar
  107. 107.
    Ulker S, McMaster D, McKeown PP, Bayraktutan U (2003) Impaired activities of antioxidant enzymes elicit endothelial dysfunction in spontaneous hypertensive rats despite enhanced vascular nitric oxide generation. Cardiovasc Res 59:488–500PubMedCrossRefGoogle Scholar
  108. 108.
    Vallance P, Leone A, Calver A, Collier J, Moncada S (1992) Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339:572–575PubMedCrossRefGoogle Scholar
  109. 109.
    Venema RC, Venema VJ, Ju H, Harris MB, Snead C, Jilling T, Dimitropoulou C, Maragoudakis ME, Catravas JD (2003) Novel complexes of guanylate cyclase with heat shock protein 90 and nitric oxide synthase. Am J Physiol Heart Circ Physiol 285:H669–H678PubMedGoogle Scholar
  110. 110.
    Wagner L, Laczy B, Tamaskó M, Mazák I, Markó L, Molnár GA, Wagner Z, Mohás M, Cseh J, Fekete A, Wittmann I (2007) Cigarette smoke-induced alterations in endothelial nitric oxide synthase phosphorylation: role of protein kinase C. Endothelium: J Endo Cell Res 14:245–255Google Scholar
  111. 111.
    Wang H, Wang AX, Liu Z, Chai W, Barrett EJ (2009) The trafficking/interaction of eNOS and caveolin-1 induced by insulin modulates endothelial nitric oxide production. Mol Endocrinol 23:1613–1623PubMedCrossRefGoogle Scholar
  112. 112.
    Wedgwood S, McMullan DM, Bekker JM, Fineman JR, Black SM (2001) Role for endothelin-1-induced superoxide and peroxynitrite production in rebound pulmonary hypertension associated with inhaled nitric oxide therapy. Circ Res 89:357–364PubMedCrossRefGoogle Scholar
  113. 113.
    Widder JD, Chen W, Li L, Dikalov S, Thony B, Hatakeyama K, Harrison DG (2007) Regulation of tetrahydrobiopterin biosynthesis by shear stress. Circ Res 101:830–838PubMedCrossRefGoogle Scholar
  114. 114.
    Xu B, Chibber R, Ruggerio D, Kohner E, Ritter J, Ferro A (2003) Impairment of vascular endothelial nitric oxide synthase activity by advanced glycation end products. The FASEB Journal 17:1289–1291PubMedCrossRefGoogle Scholar
  115. 115.
    Xu HL, Galea E, Santizo RA, Baughman VL, Pelligrino DA (2001) The key role of caveolin-1 in estrogen-mediated regulation of endothelial nitric oxide synthase function in cerebral arterioles in vivo. J Cereb Blood Flow Metab 21:907–913PubMedCrossRefGoogle Scholar
  116. 116.
    Yin G, Yan C, Berk BC (2003) Angiotensin II signaling pathways mediated by tyrosine kinases. Int J Biochem Cell Biol 35:780–783PubMedCrossRefGoogle Scholar
  117. 117.
    Yu H, Li X, Marchetto GS, Dy R, Hunter D, Calvo B, Dawson TL, Wilm M, Anderegg RJ, Graves LM, Earp HS (1996) Activation of a novel calcium-dependent protein-tyrosine kinase. Correlation with c-Jun N-terminal kinase but not mitogen-activated protein kinase activation. J Biol Chem 271:29993–29998PubMedCrossRefGoogle Scholar
  118. 118.
    Zabel U, Hausler C, Weeger M, Schmidt HH (1999) Homodimerization of soluble guanylyl cyclase subunits. Dimerization analysis using a glutathione s-transferase affinity tag. J Biol Chem 274:18149–18152PubMedCrossRefGoogle Scholar
  119. 119.
    Zanetti M, Sato J, Jost CJ, Gloviczki P, Katusic ZS, O'Brien T (2001) Gene transfer of manganese superoxide dismutase reverses vascular dysfunction in the absence but not in the presence of atherosclerotic plaque. Hum Gene Ther 12:1407–1416PubMedCrossRefGoogle Scholar
  120. 120.
    Zhang Q, Malik P, Pandey D, Gupta S, Jagnandan D, de Chantemele EB, Banfi B, Marrero MB, Rudic RD, Stepp DW, Fulton DJR (2008) Paradoxical activation of endothelial nitric oxide synthase by NADPH oxidase. Arterioscler Thromb Vasc Biol 28:1627–1633PubMedCrossRefGoogle Scholar
  121. 121.
    Zou MH, Wu Y (2008) AMP-activated protein kinase activation as a strategy for protecting vascular endothelial function. Clin Exp Pharmacol Physiol 35:535–545PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Institute for Vascular Signalling, Centre for Molecular MedicineJohann Wolfgang Goethe UniversityFrankfurt am MainGermany

Personalised recommendations