Vascular Endothelium and Blood Flow

  • R. Busse
  • I. Fleming
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 176/II)


Major advances have been made over the last decade towards the elucidation of the molecular mechanisms involved in the endothelium-dependent regulation of vascular tone and blood flow. While the primary endothelium-derived vasodilator autacoid is nitric oxide, it is clear that epoxyeicosatrienoic acids and other endothelium-derived hyperpolarising factors, as well as endothelin-1 and reactive oxygen species, play a significant role in the regulation of vascular tone and gene expression. This review is intended as an overview of the signalling mechanisms that link haemodynamic stimuli (such as shear stress and cyclic stretch) and endothelial cell perturbation to the activation of enzymes generating vasoactive autacoids.


Fluid shear stress Mechanotransduction Nitric oxide synthase PECAM-1 Tyrosine phosphatase 


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  1. Alhenc-Gelas F, Tsai SL, Callahan KS, Campbell WB, Johnson AR (1982) Stimulation of prostaglandin formation by vasoactive mediators in cultured human endothelial cells. Prostaglandins 24:723–742PubMedGoogle Scholar
  2. Alonso-Galicia M, Drummond HA, Reddy KK, Falck JR, Roman RJ (1997) Inhibition of 20-HETE production contributes to the vascular responses to nitric oxide. Hypertension 29:320–325PubMedGoogle Scholar
  3. Arai M, Imai H, Metori A, Nakagawa Y (1997) Preferential esterification of endogenously formed 5-hydroxyeicosatetraenoic acid to phospholipids in activated polymorphonuclear leukocytes. Eur J Biochem 244:513–519PubMedGoogle Scholar
  4. Awolesi M, Sessa WC, Sumpio BE (1995) Cyclic strain upregulates nitric oxide synthase in cultured bovine aortic endothelial cells. J Clin Invest 96:1449–1454PubMedGoogle Scholar
  5. 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
  6. Bagi Z, Koller A (2003) Lack of nitric oxide mediation of flow-dependent arteriolar dilation in type I diabetes is restored by sepiapterin. J Vasc Res 40:47–57PubMedGoogle Scholar
  7. 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 25:1590–1595PubMedGoogle Scholar
  8. Baron A, Frieden M, Bény JL (1997) Epoxyeicosatrienoic acids activate a high-conductance, Ca2+-dependent K+ channel on pig coronary artery endothelial cells. J Physiol (Lond) 504:537–543PubMedGoogle Scholar
  9. Bauersachs J, Popp R, Hecker M, Sauer E, Fleming I, Busse R (1996) Nitric oxide attenuates the release of endothelium-derived hyperpolarizing factor. Circulation 94:3341–3347PubMedGoogle Scholar
  10. Bec N, Gorren AC, Voelker C, Mayer B, Lange R (1998) Reaction of neuronal nitric-oxide synthase with oxygen at low temperature. Evidence for reductive activation of the oxyferrous complex by tetrahydrobiopterin. J Biol Chem 273:13502–13508PubMedGoogle Scholar
  11. Bec N, Gorren AFC, Mayer B, Schmidt PP, Andersson KK, Lange R (2000) The role of tetrahydrobiopterin in the activation of oxygen by nitric-oxide synthase. J Inorg Biochem 81:207–211PubMedGoogle Scholar
  12. Bergaya S, Meneton P, Bloch-Faure M, Mathieu E, Alhenc-Gelas F, Levy BI, Boulanger CM (2001) Decreased flow-dependent dilation in carotid arteries of tissue kallikrein-knockout mice. Circ Res 88:593–599PubMedGoogle Scholar
  13. Bergaya S, Hilgers RHP, Meneton P, Dong Y, Bloch-Faure M, Inagami T, Alhenc-Gelas F, Levy BI, Boulanger CM (2004) Flow-dependent dilation mediated by endogenous kinins requires angiotensin AT2 receptors. Circ Res 94:1623–1629PubMedGoogle Scholar
  14. Berk BC, Corson MA, Peterson TE, Tseng H (1995) Protein kinases as mediators of fluid shear stress stimulated signal transduction in endothelial cells: a hypothesis for calcium-dependent and calcium-independent events activated by flow. J Biomech 28:1439–1450PubMedGoogle Scholar
  15. 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
  16. Boo YC, Sorescu G, Boyd N, Shiojima I, Walsh K, Du J, Jo H (2002) Shear stress stimulates phosphorylation of endothelial nitric-oxide synthase at Ser1179 by Akt-independent mechanisms: role of protein kinase A. J Biol Chem 277:3388–3396PubMedGoogle Scholar
  17. Boyd NL, Park H, Yi H, Boo YC, Sorescu GP, Sykes M, Jo H (2003) Chronic shear induces caveolae formation and alters ERK and Akt responses in endothelial cells. Am J Physiol Heart Circ Physiol 285:H1113–H1122PubMedGoogle Scholar
  18. Brandes RP, Kreuzer J (2005) Vascular NADPH oxidases: molecular mechanisms of activation. Cardiovasc Res 65:16–27PubMedGoogle Scholar
  19. Budel S, Bartlett IS, Segal SS (2003) Homocellular conduction along endothelium and smooth muscle of arterioles in hamster cheek pouch: unmasking an NO wave. Circ Res 93:61–68PubMedGoogle Scholar
  20. Busse R, Fleming I (2003) Regulation of endothelium-derived vasoactive autacoid production by hemodynamic forces. Trends Pharmacol Sci 24:24–29PubMedGoogle Scholar
  21. Busse R, Mülsch A (1990) Calcium-dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin. FEBS Lett 265:133–136PubMedGoogle Scholar
  22. Busse R, Edwards G, Feletou M, Fleming I, Vanhoutte PM, Weston AH (2002) EDHF:bringing the concepts together. Trends Pharmacol Sci 23:374–380PubMedGoogle Scholar
  23. Campbell WB, Gebremedhin D, Pratt PF, Harder DR (1996) Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ Res 78:415–423PubMedGoogle Scholar
  24. Cao MY, Huber M, Beauchemin N, Famiglietti J, Albelda SM, Veillette A (1998) Regulation of mouse PECAM-1 tyrosine phosphorylation by the Src and Csk families of proteintyrosine kinases. J Biol Chem 273:15765–15772PubMedGoogle Scholar
  25. Cardone L, Carlucci A, Affaitati A, Livigni A, deCristofaro T, Garbi C, Varrone S, Ullrich A, Gottesman ME, Avvedimento EV, Feliciello A (2004) Mitochondrial AKAP121 binds and targets protein tyrosine phosphatase D1, a novel positive regulator of src signaling. Mol Cell Biol 24:4613–4626PubMedGoogle Scholar
  26. Carroll MA, Balazy M, Margiotta P, Huang DD, Falck JR, McGiff JC (1996) Cytochrome P-450-dependent HETEs: profile of biological activity and stimulation by vasoactive peptides. Am J Physiol 271:R863–R869PubMedGoogle Scholar
  27. Chang J, Musser JH, McGreggor H (1987) Phospholipase A2: function and pharmacological regulation. Biochem Pharmacol 36:2429–2436PubMedGoogle Scholar
  28. Chaytor AT, Evans WH, Griffith TM (1997) Central role of heterocellular gap junctional communication in endothelium-dependent relaxations of rabbit arteries. J Physiol (Lond) 508:561–573Google Scholar
  29. Chen CS, Tan J, Tien J (2004) Mechanotransduction at cell-matrix and cell-cell contacts. Annu Rev Biomed Eng 6:275–302PubMedGoogle Scholar
  30. Chen KD, Li YS, Kim M, Li S, Yuan S, Chien S, Shyy JYJ (1999) Mechanotransduction in response to shear stress—roles of receptor tyrosine kinases, integrins, and Shc. J Biol Chem 274:18393–18400PubMedGoogle Scholar
  31. Coleman HA, Tare M, Parkington HC (2001) K+ currents underlying the action of endothelium-derived hyperpolarizing factor in guinea-pig, rat and human blood vessels. J Physiol (Lond) 531:359–373PubMedGoogle Scholar
  32. Correa-Meyer E, Pesce L, Guerrero C, Sznajder JI (2002) Cyclic stretch activates ERK1/2 via G proteins and EGFR in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 282:L883–L891PubMedGoogle Scholar
  33. 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
  34. Cosentino F, Katusic ZS (1995) Tetrahydrobiopterin and dysfunction of endothelial nitric oxide synthase in coronary arteries. Circulation 91:139–144PubMedGoogle Scholar
  35. Cunnick JM, Mei L, Doupnik CA, Wu J (2001) Phosphotyrosines 627 and 659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) conferring binding and activation of SHP2. J Biol Chem 276:24380–24387PubMedGoogle Scholar
  36. d’Uscio LV, Milstien S, Richardson D, Smith L, Katusic ZS (2003) Long-termvitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity. Circ Res 92:88–95PubMedGoogle Scholar
  37. Dai G, Kaazempur-Mofrad MR, Natarajan S, Zhang Y, Vaughn S, Blackman BR, Kamm RD, García-Cardena G, Gimbrone MA Jr (2004) Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and-resistant regions of human vasculature. Proc Natl Acad Sci U S A 101:14871–14876PubMedGoogle Scholar
  38. Davidge ST (2001) Prostaglandin H synthase and vascular function. Circ Res 89:650–660PubMedGoogle Scholar
  39. Davies PF (1995) Flow-mediated endothelial mechanotransduction. Physiol Rev 75:519–560PubMedGoogle Scholar
  40. Davies PF, Zilberberg J, Helmke BP (2003) Spatial microstimuli in endothelial mechanosignaling. Circ Res 92:359–370PubMedGoogle Scholar
  41. De Keulenaer GW, Chappell DC, Alexander RW, Nerem RM, Griendling KK (1998) Oscillatory and steady laminar shear stress differentially affect human endothelial redox state: role of a superoxide-producing NADH oxidase. Circ Res 82:1094–1101PubMedGoogle Scholar
  42. de Wit C, Roos F, Bolz SS, Kirchhoff S, Krüger O, Willecke K, Pohl U (2000) Impaired conduction of vasodilatation along arterioles in connexin40-deficient mice. Circ Res 86:649–655PubMedGoogle Scholar
  43. DeLisser HM, Baldwin HS, Albelda SM (1997) Platelet endothelial cell adhesion molecule 1(PECAM-1/CD31): a multifunctional vascular cell adhesion molecule. Trends Cardiovascul Med 7:203–210Google Scholar
  44. Desaphy JF, Joffre M (1998) Effect of cyclic AMP on the calcium-dependent potassium conductances of rat leydig cells. Can J Physiol Pharmacol 76:649–656PubMedGoogle Scholar
  45. 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 399:601–605PubMedGoogle Scholar
  46. 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 nitric oxide synthase by fluid shear stress. Circ Res 97:1236–1244PubMedGoogle Scholar
  47. Doyle MP, Duling BR (1997) Acetylcholine induces conducted vasodilation by nitric oxide-dependent and-independent mechanisms. Am J Physiol 272:H1364–H1371PubMedGoogle Scholar
  48. 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 293:2449–2452PubMedGoogle Scholar
  49. 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 24:1796–1802PubMedGoogle Scholar
  50. Edwards G, Dora KA, Gardener MJ, Garland CJ, Weston AH (1998) K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature 396:269–272PubMedGoogle Scholar
  51. Emerson GG, Segal SS (2000a) Endothelial cell pathway for conduction of hyperpolarization and vasodilatation along hamster feed artery. Circ Res 86:94–100PubMedGoogle Scholar
  52. Emerson GG, Segal SS (2000b) Electrical coupling between endothelial cells and smooth muscle cells in hamster feed arteries: role in vasomotor control. Circ Res 87:474–479PubMedGoogle Scholar
  53. Emerson GG, Segal SS (2001) Electrical activation of endothelium evokes vasodilation and hyperpolarization along hamster feed arteries. Am J Physiol Heart Circ Physiol 280:H160–H167PubMedGoogle Scholar
  54. Esguerra M, Wang J, Foster CD, Adelman JP, North RA, Levitan IB (1994) Cloned Ca2+-dependent K+ channel modulated by a functionally associated protein kinase. Nature 369:563–565PubMedGoogle Scholar
  55. Everson WV, Smart EJ (2001) Influence of caveolin, cholesterol, and lipoproteins on nitric oxide synthase: implications for vascular disease. Trends Cardiovasc Med 11:246–250PubMedGoogle Scholar
  56. Feron O, Dessy C, Moniotte S, Desager JP, Balligand JL (1999) Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase. J Clin Invest 103:897–905PubMedGoogle Scholar
  57. Ferrero E, Belloni D, Contini P, Foglieni C, Ferrero ME, Fabbri M, Poggi A, Zocchi MR (2003) Transendothelial migration leads to protection from starvation-induced apoptosis in CD34+CD14+ circulating precursors: evidence for PECAM-1 involvement through Akt/PKB activation. Blood 101:186–193PubMedGoogle Scholar
  58. Fichtlscherer S, Dimmeler S, Breuer S, Busse R, Zeiher AM, Fleming I (2004) Inhibition of cytochrome P450 2C9 improves endothelium-dependent, nitric oxide-mediated vasodilatation in patients with coronary artery disease. Circulation 109:178–183PubMedGoogle Scholar
  59. Figueroa XF, Isakson BE, Duling BR (2004) Connexins: gaps in our knowledge of vascular function. Physiology 19:277–284PubMedGoogle Scholar
  60. Fisslthaler B, Popp R, Kiss L, Potente M, Harder DR, Fleming I, Busse R (1999) Cytochrome P450 2C is an EDHF synthase in coronary arteries. Nature 401:493–497PubMedGoogle Scholar
  61. 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 168:81–88PubMedGoogle Scholar
  62. Fisslthaler B, Popp R, Michaelis UR, Kiss L, Fleming I, Busse R (2001) Cyclic stretch enhances the expression and activity of coronary endothelium-derived hyperpolarizing factor synthase. Hypertension 38:1427–1432PubMedGoogle Scholar
  63. Fisslthaler B, Michaelis UR, Busse R, Fleming I (2003) Mechanical stimulation increases the activity and expression of cytochrome P450 2C in porcine coronary artery endothelial cells. In: Vanhoutte PM (ed) EDHF 2002. Taylor and Francis, London, pp 56–62Google Scholar
  64. Fleming I, Busse R (2003) Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol 284:R1–R12PubMedGoogle Scholar
  65. Fleming I, Hecker M, Busse R (1994) Intracellular alkalinization induced by bradykinin sustains activation of the constitutive nitric oxide synthase in endothelial cells. Circ Res 74:1220–1226PubMedGoogle Scholar
  66. 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
  67. Fleming I, Fisslthaler B, Dimmeler S, Kemp BE, Busse R (2001a) Phosphorylation of Thr495 regulates Ca2+/calmodulin-dependent endothelial nitric oxide synthase activity. Circ Res 88:e68–e75PubMedGoogle Scholar
  68. Fleming I, Fisslthaler B, Michaelis UR, Kiss L, Popp R, Busse R (2001b) The coronary endothelium-derived hyperpolarizing factor (EDHF) stimulates multiple signalling pathways and proliferation in vascular cells. Pflugers Arch 442:511–518PubMedGoogle Scholar
  69. Fleming I, Michaelis UR, Bredenkötter D, Fisslthaler B, Dehghani F, Brandes RP, Busse R (2001c) Endothelium-derived hyperpolarizing factor synthase (cytochrome P450 2C9) is a functionally significant source of reactive oxygen species in coronary arteries. Circ Res 88:44–51PubMedGoogle Scholar
  70. 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 118:4103–4111PubMedGoogle Scholar
  71. Fox RJ, Frame MD (2002) Arteriolar flow recruitment with vitronectin receptor stimulation linked to remote wall shear stress. Microvasc Res 64:414–424PubMedGoogle Scholar
  72. Fujiwara K, Masuda M, Osawa M, Kano Y, Katoh K (2001) Is PECAM-1 a mechanoresponsive molecule? Cell Struct Funct 26:11–17PubMedGoogle Scholar
  73. Fulton D, Gratton JP, 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 399:597–601PubMedGoogle Scholar
  74. 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 274:30101–30108PubMedGoogle Scholar
  75. Gan LM, Selin-Sjogren L, Doroudi R, Jern S (2000) Temporal regulation of endothelial ET-1 and eNOS expression in intact human conduit vessels exposed to different intraluminal pressure levels at physiological shear stress. Cardiovasc Res 48:168–177PubMedGoogle Scholar
  76. 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 271:27237–27240PubMedGoogle Scholar
  77. García-Cardena G, Fan R, Shah V, Sorrentino R, Cirino G, Papapetropoulos A, Sessa WC (1998) Dynamic activatiaton of endothelial nitric oxide synthase by Hsp90. Nature 292:821–824Google Scholar
  78. García-Cardena G, Comander J, Anderson KR, Blackman BR, Gimbrone MA Jr (2001) Biomechanical activation of vascular endothelium as a determinant of its functional phenotype. Proc Natl Acad Sci U S A 98:4478–4485PubMedGoogle Scholar
  79. Gauthier KM, Liu C, Popovic A, Albarwani S, Rusch NJ (2002) Freshly isolated bovine coronary endothelial cells do not express the BK Ca channel gene. J Physiol 545:829–836PubMedGoogle Scholar
  80. Gimbrone MA Jr, Topper JN, Nagel T, Anderson KR, García-Cardena G (2000) Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann NY Acad Sci 902:230–239PubMedGoogle Scholar
  81. Go YM, Park H, Maland MC, Darley-Usmar VM, Stoyanov B, Wetzker R, Jo H (1998) Phosphatidylinositol 3-kinase gamma mediates shear stress-dependent activation of JNK in endothelial cells. Am J Physiol 275:H1898–H1904PubMedGoogle Scholar
  82. Gokce N, Keaney JF Jr, Frei B, Holbrook M, Olesiak M, Zachariah BJ, Leeuwenburgh C, Heinecke JW, Vita JA (1999) Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 99:3234–3240PubMedGoogle Scholar
  83. 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 361:193–201PubMedGoogle Scholar
  84. Granville DJ, Tashakkor B, Takeuchi C, Gustafsson AB, Huang C, Sayen MR, Wentworth P Jr, Yeager M, Gottlieb RA (2004) Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors. Proc Natl Acad Sci U S A 101:1321–1326PubMedGoogle Scholar
  85. Griffith TM, Taylor HJ (1999) Cyclic AMP mediates EDHF-type relaxations of rabbit jugular vein. Biochem Biophys Res Commun 263:52–57PubMedGoogle Scholar
  86. Groves P, Kurz S, Just H, Drexler H (1995) Role of endogenous bradykinin in human coronary vasomotor control. Circulation 92:3424–3430PubMedGoogle Scholar
  87. Gu H, Neel BG (2003) The “Gab” in signal transduction. Trends Cell Biol 13:122–13PubMedGoogle Scholar
  88. Gudi S, Huvar I, White CR, McKnight NL, Dusserre N, Boss GR, Frangos JA (2003) Rapid activation of Ras by fluid flow is mediated by Gαq and Gβγ subunits of heterotrimeric G proteins in human endothelial cells. Arterioscler Thromb Vasc Biol 23:994–1000PubMedGoogle Scholar
  89. Harada N, Masuda M, Fujiwara K (1995) Fluid flow and osmotic stress induce tyrosine phosphorylation of an endothelial cell 128 kDa surface glycoprotein. Chin J Biochem Biophys 214:69–74Google Scholar
  90. Harder DR, Gebremedhin D, Narayanan J, Jefcoat C, Falck JR, Campbell WB, Roman R (1994) Formation and action of a P-450 4A metabolite of arachidonic acid in cat cerebral microvessels. Am J Physiol 266:H2098–H2107PubMedGoogle Scholar
  91. Harder DR, Lange AR, Gebremedhin D, Birks EK, Roman RJ (1997) Cytochrome P450 metabolites of arachidonic acid as intracellular signaling molecules in vascular tissue. J Vasc Res 34:237–243PubMedGoogle Scholar
  92. Harris MB, Ju H, Venema VJ, Liang H, Zou R, Michell BJ, Chen ZP, Kemp BE, Venema RC (2001) Reciprocal phosphorylation and regulation of the endothelial nitric oxide synthase in response to bradykinin stimulation. J Biol Chem 19:16587–16591Google Scholar
  93. Harrison DG, Sayegh HS, Ohara Y, Inoue N, Venema RC (1996) Regulation of expression of the endothelial cell nitric oxide synthase. Clin Exp Pharmacol Physiol 23:251–255PubMedGoogle Scholar
  94. Helmke BP, Rosen AB, Davies PF (2003) Mapping mechanical strain of an endogenous cytoskeletal network in living endothelial cells. Biophys J 84:2691–2699PubMedGoogle Scholar
  95. Hercule HC, Wang MH, Oyekan AO (2003) Contribution of cytochrome P450 4A isoforms to renal functional response to inhibition of nitric oxide production in the rat. J Physiol 551:971–979PubMedGoogle Scholar
  96. Hishikawa K, Nakaki T, Marumo T, Suzuki H, Kato R, Saruta T (1995) Pressure enhances endothelin-1 release from cultured human endothelial cells. Hypertension 25:449–452PubMedGoogle Scholar
  97. Hoep. B, Rodenwaldt B, Pohl U, de Wit C (2002) EDHF, but not NO or prostaglandins, is critical to evoke a conducted dilation upon ACh in hamster arterioles. Am J Physiol Heart Circ Physiol 283:H996–H1004Google Scholar
  98. Hoyer J, Köhler R, Distler A (1998) Mechanosensitive Ca2+ oscillations and STOC activation in endothelial cells. FASEB J 12:359–366PubMedGoogle Scholar
  99. Huang A, Vita JA, Venema RC, Keaney JF Jr (2000) Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. J Biol Chem 275:17399–17406PubMedGoogle Scholar
  100. Huang A, Sun D, Jacobson A, Carroll MA, Falck JR, Kaley G (2005) Epoxyeicosatrienoic acids are released to mediate shear stress-dependent hyperpolarization of arteriolar smooth muscle. Circ Res 96:376–383PubMedGoogle Scholar
  101. Hungerford JE, Sessa WC, Segal SS (2000) Vasomotor control in arterioles of the mouse cremaster muscle. FASEB J 14:197–207PubMedGoogle Scholar
  102. Hurshman AR, Krebs C, Edmondson DE, Huynh BH, Marletta MA (1999) Formation of a pterin radical in the reaction of the heme domain of inducible nitric oxide synthase with oxygen. Biochemistry 38:15689–15696PubMedGoogle Scholar
  103. Hwang J, Saha A, Boo YC, Sorescu GP, McNally JS, Holland SM, Dikalov S, Giddens DP, Griendling KK, Harrison DG, Jo H (2003) Oscillatory shear stress stimulates endothelial production of O2 from p47phox-dependent NAD (P)H oxidases, leading to monocyte adhesion. J Biol Chem 278:47291–47298PubMedGoogle Scholar
  104. Ihlemann N, Rask-Madsen C, Perner A, Dominguez H, Hermann T, Kober L, Torp-Pedersen C (2003) Tetrahydrobiopterin restores endothelial dysfunction induced by an oral glucose challenge in healthy subjects. Am J Physiol Heart Circ Physiol 285:H875PubMedGoogle Scholar
  105. Ilan N, Madri JA (2003) PECAM-1: old friend, new partners. Curr Opin Cell Biol 15:515–524PubMedGoogle Scholar
  106. Imig JD, Zou AP, Stec DE, Harder DR, Falck JR, Roman RJ (1996) Formation and actions of 20-hydroxyeicosatetraenoic acid in rat renal arterioles. Am J Physiol 270:R217–R227PubMedGoogle Scholar
  107. Imig JD, Inscho EW, Deichmann PC, Reddy KM, Falck JR (1999) Afferent arteriolar vasodilation to the sulfonimide analog of 11,12-epoxyeicosatrienoic acid involves protein kinase A. Hypertension 33:408–413PubMedGoogle Scholar
  108. Ingber DE (2003) Tensegrity I. Cell structure and hierarchical systems biology. J Cell Sci 116:1157–1173PubMedGoogle Scholar
  109. Jayachandran M, Hayashi T, Sumi D, Iguchi A, Miller VM (2001) Temporal effects of 17betaestradiol on caveolin-1mRNAand protein in bovine aortic endothelial cells. Am J Physiol Heart Circ Physiol 281:H1327–H1333PubMedGoogle Scholar
  110. Jin ZG, Ueba H, Tanimoto T, Lungu AO, Frame MD, Berk BC (2003) Ligand-independent activation of vascular endothelial growth factor receptor 2 by fluid shear stress regulates activation of endothelial nitric oxide synthase. Circ Res 93:354–363PubMedGoogle Scholar
  111. 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 280:12305–12309PubMedGoogle Scholar
  112. Johnson LR, Rush JWE, Turk JR, Price EM, Laughlin MH (2001) Short-term exercise training increases ACh-induced relaxation and eNOS protein in porcine pulmonary arteries. J Appl Physiol 90:1102–1110PubMedGoogle Scholar
  113. Jung O, Schreiber JG, Geiger H, Pedrazzini T, Busse R, Brandes RP (2004) gp91PhoxcontainingNADPH oxidase mediates endothelial dysfunction in renovascular hypertension. Circulation 109:1795–1801PubMedGoogle Scholar
  114. Kanai AJ, Strauss HC, Truskey GA, Crews AL, Grunfeld S, Malinski T (1995) Shear stress induces ATP-independent transient nitric oxide release from vascular endothelial cells, measured directly with a porphyrinic microsensor. Circ Res 77:284–293PubMedGoogle Scholar
  115. Kano Y, Katoh K, Fujiwara K (2000) Lateral zone of cell-cell adhesion as the major fluid shear stress-related signal transduction site. Circ Res 86:425–433PubMedGoogle Scholar
  116. Karara A, Wei S, Spady D, Swift L, Capdevila JH, Falck JR (1992) Arachidonic acid epoxygenase: structural characterization and quantification of epoxyeicosatrienoates in plasma. Biochem Biophys Res Commun 182:1320–1325PubMedGoogle Scholar
  117. Kaufman DA, Albelda SM, Sun J, Davies PF (2004) Role of lateral cell-cell border location and extracellular/transmembrane domains in PECAM/CD31 mechanosensation. Biochem Biophys Res Commun 320:1076–1081PubMedGoogle Scholar
  118. Kim F, Gallis B, Corson MA (2001) TNF-alpha inhibits flow and insulin signaling leading to NO production in aortic endothelial cells. Am J Physiol Cell Physiol 280:C1057–C1065PubMedGoogle Scholar
  119. Kim F, Tysseling KA, Rice J, Pham M, Haji L, Gallis BM, Baas AS, Paramsothy P, Giachelli CM, Corson MA, Raines EW (2005) Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKβ. Arterioscler Thromb Vasc Biol 25:989–994PubMedGoogle Scholar
  120. Kleinert H, Wallerath T, Euchenhofer C, Ihrig-Biedert I, Li H, Förstermann U (1998) Estrogens increase transcription of the human endothelial NO synthase gene: analysis of the transcription factors involved. Hypertension 31:582–588PubMedGoogle Scholar
  121. Kogata N, Masuda M, Kamioka Y, Yamagishi A, Endo A, Okada M, Mochizuki N (2003) Identification of Fer tyrosine kinase localized on microtubules as a platelet endothelial cell adhesion molecule-1 phosphorylating kinase in vascular endothelial cells. Mol Biol Cell 14:3553–3564PubMedGoogle Scholar
  122. Kojda G, Cheng YC, Burchfield J, Harrison DG (2001) Dysfunctional regulation of endothelial nitric oxide synthase (eNOS) expression in response to exercise in mice lacking one eNOS gene. Circulation 103:2839–2844PubMedGoogle Scholar
  123. Kuchan MJ, Frangos JA (1993) Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells. Am J Physiol 264:H150–H156PubMedGoogle Scholar
  124. Kuchan MJ, Frangos JA (1994) Role of calcium and calmodulin in flow-induced nitric oxide production in endothelial cells. Am J Physiol 266:C628–C636PubMedGoogle Scholar
  125. Kuzkaya N, Weissmann N, Harrison DG, Dikalov S (2003) Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem 278:22546–22554PubMedGoogle Scholar
  126. 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
  127. Lassegue B, Griendling KK (2004) Reactive oxygen species in hypertension; an update. Am J Hypertens 17:852–860PubMedGoogle Scholar
  128. Laughlin MH, Pollock JS, Amann JF, Hollis ML, Woodman CR, Price EM (2001) Training induces nonuniform increases in eNOS content along the coronary arterial tree. J Appl Physiol 90:501–510PubMedGoogle Scholar
  129. Laursen JB, Somers M, Kurz S, McCann L, Warnholtz A, Freeman BA, Tarpey M, Fukai T, Harrison DG (2001) Endothelial regulation of vasomotion in apoE-deficient mice: implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation 103:1282–1288PubMedGoogle Scholar
  130. Lauth M, Berger MM, Cattaruzza M, Hecker M (2000) Elevated perfusion pressure upregulates endothelin-1 and endothelin B receptor expression in the rabbit carotid artery. Hypertension 35:648–654PubMedGoogle Scholar
  131. Lavallee M, Takamura M, Parent R, Thorin E (2001) Crosstalk between endothelin and nitric oxide in the control of vascular tone. Heart Fail Rev 6:365–376Google Scholar
  132. Lee HJ, Koh GY (2003) Shear stress activates Tie2 receptor tyrosine kinase in human endothelial cells. Biochem Biophys Res Commun 304:399–404PubMedGoogle Scholar
  133. Lehoux S, Esposito B, Merval R, Tedgui A (2005) Differential regulation of vascular focal adhesion kinase by steady stretch and pulsatility. Circulation 111:643–649PubMedGoogle Scholar
  134. Li PL, Campbell WB (1997) Epoxyeicosatrienoic acids activate K+ channels in coronary smooth muscle through a guanine nucleotide binding protein. Circ Res 80:877–884PubMedGoogle Scholar
  135. Li S, Kim M, Hu YL, Jalali S, Schlaepfer DD, Hunter T, Chien S, Shyy JY (1997) Fluid shear stress activation of focal adhesion kinase—linking to mitogen-activated protein kinases. J Biol Chem 272:30455–30462PubMedGoogle Scholar
  136. Li S, Butler P, Wang Y, Hu Y, Han DC, Usami S, Guan JL, Chien S (2002) The role of the dynamics of focal adhesion kinase in the mechanotaxis of endothelial cells. Proc Natl Acad Sci U S A 99:3546–3551PubMedGoogle Scholar
  137. Loll P, Garavito M (1994) The isoforms of cyclooxygenase: structure and function. Expert Opin Investig Drugs 3:1171–1180Google Scholar
  138. Looft-Wilson RC, Payne GW, Segal SS (2004) Connexin expression and conducted vasodilation along arteriolar endothelium in mouse skeletal muscle. J Appl Physiol 97:1152–1158PubMedGoogle Scholar
  139. Lückhoff A, Pohl U, Mülsch A, Busse R (1988) Differential role of extra-and intracellular calcium in the release of EDRF and prostacyclin from cultured endothelial cells. Br J Pharmacol 95:189–196PubMedGoogle Scholar
  140. Lungu AO, Jin ZG, Yamawaki H, Tanimoto T, Wong C, Berk BC (2004) Cyclosporin A inhibits flow-mediated activation of endothelial nitric oxide synthase by altering cholesterol content in caveolae. J Biol Chem 279:48794–48800PubMedGoogle Scholar
  141. Ma YH, Gebremedhin D, Schwartzman ML, Falck JR, Clark JE, Masters BS, Harder DR, Roman RJ (1993) 20-Hydroxyeicosatetraenoic acid is an endogenous vasoconstrictor of canine renal arcuate arteries. Circ Res 72:126–136PubMedGoogle Scholar
  142. Macritchie AN, Jun SS, Chen Z, German Z, Yuhanna IS, Sherman TS, Shaul PW (1997) Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium. Circ Res 81:355–362PubMedGoogle Scholar
  143. Makondo K, Kimura K, Kitamura N, Kitamura T, Yamaji D, Jung BD, Saito M (2003) Hepatocyte growth factor activates endothelial nitric oxide synthase by Ca(2+)-and phosphoinositide 3-kinase/Akt-dependent phosphorylation in aortic endothelial cells. Biochem J 374:63–69PubMedGoogle Scholar
  144. Malek AM, Izumo S (1992) Physiological fluid shear stress causes downregulation of endothelin 1 mRNA in bovine aortic endothelium. Am J Physiol 263:C389–C396PubMedGoogle Scholar
  145. Malek AM, Greene AL, Izumo S (1993) Regulation of endothelin 1 gene by fluid shear stress is transcriptionally mediated and independent of protein kinase C and cAMP. Proc Natl Acad Sci U S A 90:5999–6003PubMedGoogle Scholar
  146. Marcelin-Jimenez G, Escalante B (2001) Functional and cellular interactions between nitric oxide and prostacyclin. Comp Biochem Physiol C Toxicol Pharmacol 129:349–359PubMedGoogle Scholar
  147. Matoba T, Shimokawa H, Nakashima M, Hirakawa Y, Mukai Y, Hirano K, Kanaide H, Takeshita A (2000) Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. J Clin Invest 106:1521–1530PubMedGoogle Scholar
  148. Matoba T, Shimokawa H, Kubota H, Morikawa K, Fujiki T, Kunihiro I, Mukai Y, Hirakawa Y, Takeshita A (2002) Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in human mesenteric arteries. Biochem Biophys Res Commun 209:909–913Google Scholar
  149. McCormick SM, Whitson PA, Wu KK, McIntire LV (2000) Shear stress differentially regulates PGHS-1 and PGHS-2 protein levels in human endothelial cells. Ann Biomed Eng 28:824–833PubMedGoogle Scholar
  150. McCormick SM, Eskin SG, McIntire LV, Teng CL, Lu CM, Russell CG, Chittur KK (2001) DNA microarray reveals changes in gene expression of shear stressed human umbilical vein endothelial cells. Proc Natl Acad Sci U S A 98:8955–8960PubMedGoogle Scholar
  151. McNeill AM, Kim N, Duckles SP, Krause DN, Kontos HA (1999) Chronic estrogen treatment increases levels of endothelial nitric oxide synthase protein in rat cerebral microvessels. Stroke 30:2186–2190PubMedGoogle Scholar
  152. Meneton P, Bloch-Faure M, Hagege AA, Ruetten H, Huang W, Bergaya S, Ceiler D, Gehring D, Martins I, Salmon G, Boulanger CM, Nussberger J, Crozatier B, Gasc JM, Heudes D, Bruneval P, Doetschman T, Menard J, Alhenc-Gelas F (2001) Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice. Proc Natl Acad Sci U S A 98:2634–2639PubMedGoogle Scholar
  153. Michel JB, Feron O, Sacks D, Michel T (1997) Reciprocal regulation of endothelial nitricoxide synthase by Ca2+-calmodulin and caveolin. J Biol Chem 272:15583–15586PubMedGoogle Scholar
  154. 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 276:17625–17628PubMedGoogle Scholar
  155. Miura H, Bosnjak JJ, Ning G, Saito T, Miura M, Gutterman DD (2003) Role for hydrogen peroxide in flow-induced dilation of human coronary arterioles. Circ Res 92:31e–340Google Scholar
  156. Morawietz H, Talanow R, Szibor M, Rueckschloss U, Schubert A, Bartling B, Darmer D, Holtz J (2000) Regulation of the endothelin system by shear stress in human endothelial cells. J Physiol (Lond) 525:761–770PubMedGoogle Scholar
  157. Newman PJ (1999) Switched at birth: a new family for PECAM-1. J Clin Invest 103:5–9PubMedGoogle Scholar
  158. Newman PJ, Newman DK (2003) Signal transduction pathways mediated by PECAM-1: new roles for an old molecule in platelet and vascular cell biology. Arterioscler Thromb Vasc Biol 23:953–964PubMedGoogle Scholar
  159. Nishida K, Hirano T (2003) The role of Gab family scaffolding adapter proteins in the signal transduction of cytokine and growth factor receptors. Cancer Sci 94:1029–1033PubMedGoogle Scholar
  160. Noria S, Cowan DB, Gotlieb AI, Langille BL (1999) Transient and steady-state effects of shear stress on endothelial cell adherens junctions. Circ Res 85:504–514PubMedGoogle Scholar
  161. Oeckler RA, Kaminski PM, Wolin MS (2003) Stretch enhances contraction of bovine coronary arteries via an NAD(P)H oxidase-mediated activation of the extracellular signalregulated kinase mitogen-activated protein kinase cascade. Circ Res 92:23–31PubMedGoogle Scholar
  162. Olesen SP, Clapham DE, Davies PF (1988) Haemodynamic shear stress activates aK+ current in vascular endothelial cells. Nature 331:168–170PubMedGoogle Scholar
  163. Osanai T, Fujita N, Fujiwara N, Nakano T, Takahashi K, Guan W, Okumura K (2000) Cross talk of shear-induced production of prostacyclin and nitric oxide in endothelial cells. Am J Physiol Heart Circ Physiol 278:H233–H238PubMedGoogle Scholar
  164. Osawa M, Masuda M, Harada N, Lopes RB, Fujiwara K (1997) Tyrosine phosphorylation of platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) in mechanically stimulated vascular endothelial cells. Eur J Cell Biol 72:229–237PubMedGoogle Scholar
  165. 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 158:773–785PubMedGoogle Scholar
  166. Park H, Go YM, John PL, Maland MC, Lisanti MP, Abrahamson DR, Jo H (1998) Plasma membrane cholesterol is a key molecule in shear stress-dependent activation of extracellular signal-regulated kinase. J Biol Chem 273:32304–32311PubMedGoogle Scholar
  167. Pellegatta F, Chierchia SL, Zocchi MR (1998) Functional association of platelet endothelial cell adhesion molecule-1 and phosphoinositide 3-kinase in human neutrophils. J Biol Chem 273:27768–27771PubMedGoogle Scholar
  168. 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 269:165–171PubMedGoogle Scholar
  169. Pohl U, de Wit C (1999) A unique role of NO in the control of blood flow. News Physiol Sci 14:74–80PubMedGoogle Scholar
  170. Popp R, Bauersachs J, Hecker M, Fleming I, Busse R (1996) A transferable, β-naphthoflavone-inducible, hyperpolarizing factor is synthesized by native and cultured porcine coronary endothelial cells. J Physiol (Lond) 497:699–709PubMedGoogle Scholar
  171. Popp R, Fleming I, Busse R (1998) Pulsatile stretch in coronary arteries elicits release of endothelium-derived hyperpolarizing factor: a modulator of arterial compliance. Circ Res 82:696–703PubMedGoogle Scholar
  172. Popp R, Brandes RP, Ott G, Busse R, Fleming I (2002) Dynamic modulation of interendothelial gap junctional communication by 11,12-epoxyeicosatrienoic acid. Circ Res 90:800–806PubMedGoogle Scholar
  173. Qiu Y, Tarbell JM (2000) Interaction between wall shear stress and circumferential strain affects endothelial cell biochemical production. J Vasc Res 37:147–157PubMedGoogle Scholar
  174. 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 276:38121–38138PubMedGoogle Scholar
  175. Rizzo V, McIntosh DP, Oh P, Schnitzer JE (1999) In situ flow activates endothelial nitric oxide synthase in luminal caveolae of endothelium with rapid caveolin dissociation and calmodulin association. J Biol Chem 273:34724–34729Google Scholar
  176. Rizzo V, Morton C, DePaola N, Schnitzer JE, Davies PF (2003) Recruitment of endothelial caveolae into mechanotransduction pathways by flow conditioning in vitro. AmJ Physiol Heart Circ Physiol 285:H1720–H1729Google Scholar
  177. Rosales OR, Isales CM, Barrett PQ, Brophy C, Sumpio BE (1997) Exposure of endothelial cells to cyclic strain induces elevations of cytosolic Ca2+ concentration through mobilization of intracellular and extracellular pools. Biochem J 326:385–392PubMedGoogle Scholar
  178. Rupnow HL, Phernetton TM, Shaw CE, Modrick ML, Bird IM, Magness RR (2001) Endothelial vasodilator production by uterine and systemic arteries. VII. Estrogen and progesterone effects on eNOS. Am J Physiol Heart Circ Physiol 280:H1699–H1705PubMedGoogle Scholar
  179. Schobersberger W, Friedrich F, Hoffmann G, Volkl H, Dietl P (1997) Nitric oxide donors inhibit spontaneous depolarizations by L-type Ca2+ currents in alveolar epithelial cells. Am J Physiol 272:L1092–L1097PubMedGoogle Scholar
  180. Schrör K (1985) Prostaglandins, other eicosanoids and endothelial cells. Basic Res Cardiol 80:502–514PubMedGoogle Scholar
  181. Schubert W, Frank PG, Woodman SE, Hyogo H, Cohen DE, Chow CW, Lisanti MP (2002) Microvascular hyperpermeability in caveolin-1 (−/−) knock-out mice. Treatment with a specific nitric oxide synthase inhibitor, l-NAME, restores normal microvascular permeability in Cav-1 null mice. J Biol Chem 277:40091–40098PubMedGoogle Scholar
  182. Shay-Salit A, Shushy M, Wolfovitz E, Yahav H, Breviario F, Dejana E, Resnick N (2002) VEGF receptor 2 and the adherens junction as a mechanical transducer in vascular endothelial cells. Proc Natl Acad Sci U S A 99:9462–9467PubMedGoogle Scholar
  183. Shikata Y, Rios A, Kawkitinarong K, DePaola N, Garcia JG, Birukov KG (2005) Differential effects of shear stress and cyclic stretch on focal adhesion remodeling, site-specific FAK phosphorylation, and small GTPases in human lung endothelial cells. Exp Cell Res 304:40–49PubMedGoogle Scholar
  184. Shinozaki K, Kashiwagi A, Nishio Y, Okamura T, Yoshida Y, Masada M, Toda N, Kikkawa R (1999) Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent relaxation through nitric oxide/O2 imbalance in insulin-resistant rat aorta. Diabetes 48:2437–2445PubMedGoogle Scholar
  185. Shinozaki K, Nishio Y, Okamura T, Yoshida Y, Maegawa H, Kojima H, Masada M, Toda N, Kikkawa R, Kashiwagi A (2000) Oral administration of tetrahydrobiopterin prevents endothelial dysfunction and vascular oxidative stress in the aortas of insulin-resistant rats. Circ Res 87:566–573PubMedGoogle Scholar
  186. Smith AR, Visioli F, Hagen TM (2002) Vitamin C matters: increased oxidative stress in cultured human aortic endothelial cells without supplemental ascorbic acid. FASEB J 16:1102–1104PubMedGoogle Scholar
  187. Stroes E, Kastelein J, Cosentino F, Erkelens W, Wever R, Koomans H, Lüscher T, Rabelink T (1998) Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest 99:41–46Google Scholar
  188. Stuehr D, Pou S, Rosen GM (2001) Oxygen reduction by nitric-oxide synthases. J Biol Chem 276:14533–14536PubMedGoogle Scholar
  189. Sumpio BE, Yun S, Cordova AC, Haga M, Zhang J, Koh Y, Madri JA (2005) MAP Kinases (ERK1/2, p38) and AKTcan be phosphorylated by shear stress independently of PECAM-1 (CD31) in vascular endothelial cells. J Biol Chem 280:11185–11191PubMedGoogle Scholar
  190. Taddei S, Galetta F, Virdis A, Ghiadoni L, Salvetti G, Franzoni F, Giusti C, Salvetti A (2000) Physical activity prevents age-related impairment in nitric oxide availability in elderly athletes. Circulation 101:2896–2901PubMedGoogle Scholar
  191. Takeuchi T, Kishi M, Ishii T, Nishio H, Hata F (1996) Nitric oxide-mediated relaxation without concomitant changes incyclic GMP content of ratproximal colon. Br J Pharmacol 117:1204–1208PubMedGoogle Scholar
  192. Tamada M, Sheetz MP, Sawada Y (2004) Activation of a signaling cascade by cytoskeleton stretch. Dev Cell 7:709–718PubMedGoogle Scholar
  193. Teichert AM, Karantzoulis-Fegaras F, Wang Y, Mawji IA, Bei X, Gnanapandithen K, Marsden PA (1998) Characterization of the murine endothelial nitric oxide synthase promoter. Biochim Biophys Acta 1443:352–357PubMedGoogle Scholar
  194. Teichert AM, Miller TL, Tai SC, Wang Y, Bei X, Robb GB, Phillips MJ, Marsden PA (2000) In vivo expression profile of an endothelial nitric oxide synthase promoter-reporter transgene. Am J Physiol Heart Circ Physiol 278:H1352–H1361PubMedGoogle Scholar
  195. Testa M, Ennezat PV, Vikstrom KL, Demopoulos L, Gentilucci M, Loperfido F, Fanelli R, Kitsis RN, Leinwand LA, LeJemtel TH (2000) Modulation of vascular endothelial gene expression by physical training in patients with chronic heart failure. Ital Heart J 1:426–430PubMedGoogle Scholar
  196. Thomas DD, Miranda KM, Colton CA, Citrin D, Espey MG, Wink DA (2003) Heme proteins and nitric oxide (NO): the neglected, eloquent chemistry in NO redox signaling and regulation. Antioxid Redox Signal 5:307–317PubMedGoogle Scholar
  197. Thomas GD, Segal SS (2004) Neural control of muscle blood flow during exercise. J Appl Physiol 97:731–738PubMedGoogle Scholar
  198. Topper JN, Cai J, Falb D, Gimbrone MA (1996) Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci USA 93:10417–10422PubMedGoogle Scholar
  199. Touyz RM (2004) Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what Is the clinical significance? Hypertension 44:248–252PubMedGoogle Scholar
  200. Tschumperlin DJ, Dai G, Maly IV, Kikuchi T, Laiho LH, McVittie AK, Haley KJ, Lilly CM, So PTC, Lauffenburger DA, Kamm RD, Drazen JM (2004) Mechanotransduction through growth-factor shedding into the extracellular space. Nature 429:83–86PubMedGoogle Scholar
  201. Uematsu M, Ohara Y, Navas JP, Nishida K, Murphy TJ, Alexander RW, Nerem RM, Harrison DG (1995) Regulation of endothelial cell nitric oxide synthase mRNA expression by shear stress. Am J Physiol 269:C1371–C1378PubMedGoogle Scholar
  202. Ungvari Z, Csiszar A, Huang A, Kaminski PM, Wolin MS, Koller A (2003) High pressure induces superoxide production in isolated arteries via protein kinase C-dependent activation of NAD(P)H oxidase. Circulation 108:1253–1258PubMedGoogle Scholar
  203. Vuori K (1998) Integrin signalling: tyrosine phosphorylation events in focal adhesions. J Membr Biol 165:191–199PubMedGoogle Scholar
  204. Wagner F, Buz S, Neumeyer HH, Hetzer R, Hocher B (2004) Nitric oxide inhalation modulates endothelin-1 plasma concentration gradients following left ventricular assist device implantation. J Cardiovasc Pharmacol 44:S89–S91PubMedGoogle Scholar
  205. Wang X, Barber DA, Lewis DA, McGregor CG, Sieck GC, Fitzpatrick LA, Miller VM (1997) Gender and transcriptional regulation of NO synthase and ET-1 in porcine aortic endothelial cells. Am J Physiol 273:H1962–H1967PubMedGoogle Scholar
  206. Wang Y, Miao H, Li S, Chen KD, Li YS, Yuan S, Shyy JYJ, Chien S (2002) Interplay between integrins and FLK-1 in shear stress-induced signaling. Am J Physiol Cell Physiol 283:C1540–C1547PubMedGoogle Scholar
  207. Watanabe H, Vriens J, Prenen J, Droogmans G, Voets T, Nilius B (2003) Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature 424:434–438PubMedGoogle Scholar
  208. Wei CC, Wang ZQ, Durra D, Hemann C, Hille R, Garcin ED, Getzoff ED, Stuehr DJ (2005) The three nitric-oxide synthases differ in their kinetics of tetrahydrobiopterin radical formation, heme-dioxy reduction, and arginine hydroxylation. J Biol Chem 280:8929–8935PubMedGoogle Scholar
  209. Weidner KM, Di Cesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W (1996) Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature 384:173–176PubMedGoogle Scholar
  210. Welsh DG, Segal SS (1998) Endothelial and smooth muscle cell conduction in arterioles controlling blood flow. Am J Physiol Heart Circ Physiol 43:H178–H186Google Scholar
  211. Welsh DG, Segal SS (2000) Role of EDHF in conduction of vasodilation along hamster cheek pouch arterioles in vivo. Am J Physiol Heart Circ Physiol 278:H1832–H1839PubMedGoogle Scholar
  212. Wolin MS, Gupte SA, Oeckler RA (2002) Superoxide in the vascular system. J Vasc Res 39:191–207PubMedGoogle Scholar
  213. Xia J, Duling BR (1995) Electromechanical coupling and the conducted vasomotor response. Am J Physiol 269:H2022–H2030PubMedGoogle Scholar
  214. Xia J, Duling BR (1998) Patterns of excitation-contraction coupling in arterioles: dependence on time and concentration. Am J Physiol 274:H323–H330PubMedGoogle Scholar
  215. Yamamoto K, Sokabe T, Watabe T, Miyazono K, Yamashita JK, Obi S, Ohura N, Matsushita A, Kamiya A, Ando J (2005) Fluid shear stress induces differentiation of Flk-1-positive embryonic stem cells into vascular endothelial cells in vitro. Am J Physiol Heart Circ Physiol 288:H1915–H1924PubMedGoogle Scholar
  216. Yamamoto Y, Imaeda K, Suzuki H (1999) Endothelium-dependent hyperpolarization and intercellular electrical coupling in guinea-pig mesenteric arterioles. J Physiol 514:505–513PubMedGoogle Scholar
  217. Yang S, Bae L, Zhang L (2000) Estrogen increases eNOS and NOx release in human coronary artery endothelium. J Cardiovasc Pharmacol 36:242–247PubMedGoogle Scholar
  218. Yashiro Y, Duling BR (2000) Integrated Ca2+ signaling between smooth muscle and endothelium of resistance vessels. Circ Res 87:1048–1054PubMedGoogle Scholar
  219. Ziegler T, Silacci P, Harrison VJ, Hayoz D (1998a) Nitric oxide synthase expression in endothelial cells exposed to mechanical forces. Hypertension 32:351–355PubMedGoogle Scholar
  220. Ziegler T, Bouzourene K, Harrison VJ, Brunner HR, Hayoz D (1998b) Influence of oscillatory and unidirectional flow environments on the expression of endothelin and nitric oxide synthase in cultured endothelial cells. Arterioscler Thromb Vasc Biol 18:686–692PubMedGoogle Scholar
  221. Zou AP, Fleming JT, Falck JR, Jacobs ER, Gebremedhin D, Harder DR, Roman RJ (1996) 20-HETE is an endogenous inhibitor of the large-conductance Ca2+-activated K+ channel in renal arterioles. Am J Physiol 270:R228–R237PubMedGoogle Scholar
  222. Zygmunt PM, Högestätt ED (1996) Role of potassium channels in endothelium-dependent relaxation resistant to nitroarginine in the rat hepatic artery. Br J Pharmacol 117:1600–1606PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2006

Authors and Affiliations

  • R. Busse
    • 1
  • I. Fleming
    • 1
  1. 1.Vascular Signalling Group, Institut für Kardiovaskuläre PhysiologieKlinikum der J.W. Goethe-UniversitätFrankfurt am MainGermany

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