Skip to main content
SpringerLink
Log in
Book cover

Textbook of Pulmonary Vascular Disease pp 167–195Cite as

Endothelial Regulation of Pulmonary Vascular Tone

  • Chapter
  • First Online:

  • 416 Accesses

Abstract

This chapter focuses on the central significance of the pulmonary endothelium in the control of pulmonary vascular tone in pulmonary development, homeostasis, and pathophysiological processes. We review the upstream stimuli known to regulate the expression and activity of endothelium-specific mediators of vascular tone. Subsequently, we focus on the known actions of the endothelium-derived vasoactive effectors most important for the balance of control of vasomotor tone – vasodilators (nitric oxide and prostacyclin) and vasoconstrictors (thromoboxane A2 and endothelin). Additional mediators that may affect pulmonary vasomotor tone and endothelium-derived hyperpolarizing factor related activity are discussed, along with more poorly characterized effectors. Finally, the complex balance of these vasoactive factors and the intersection of their downstream signaling pathways is presented in the context of prototypical in vivo physiological and pathophysiological processes in the pulmonary circulation.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   349.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Cocks TM, Angus JA (1983) Endothelium-dependent relaxation of coronary arteries by noradrenaline and serotonin. Nature 305:627–630

    PubMed  CAS  Google Scholar 

  2. Liu SF, Crawley DE, Evans TW, Barnes PJ (1991) Endogenous nitric oxide modulates adrenergic neural vasoconstriction in guinea-pig pulmonary artery. Br J Pharmacol 104:565–569

    PubMed  CAS  Google Scholar 

  3. Greenberg S, Diecke FP, Peevy K, Tanaka TP (1989) The ­endothelium modulates adrenergic neurotransmission to canine pulmonary arteries and veins. Eur J Pharmacol 162:67–80

    PubMed  CAS  Google Scholar 

  4. Hu ZW, Miller JW, Hoffman BB (1994) Induction of enhanced release of endothelium-derived relaxing factor after prolonged exposure to alpha-adrenergic agonists: role in desensitization of smooth muscle contraction. J Cardiovasc Pharmacol 23:337–343

    PubMed  CAS  Google Scholar 

  5. Fineman JR, Heymann MA, Soifer SJ (1991) N ω-nitro-L-arginine attenuates endothelium-dependent pulmonary vasodilation in lambs. Am J Physiol Heart Circ Physiol 260:H1299–H1306

    CAS  Google Scholar 

  6. McMahon TJ, Hood JS, Bellan JA, Kadowitz PJ (1991) N ­ω-nitro-L-arginine methyl ester selectively inhibits pulmonary vasodilator responses to acetylcholine and bradykinin. J Appl Physiol 71:2026–2031

    PubMed  CAS  Google Scholar 

  7. Liu SF, Crawley DE, Rohde JA, Evans TW, Barnes PJ (1992) Role of nitric oxide and guanosine 3′,5′-cyclic monophosphate in ­mediating nonadrenergic, noncholinergic relaxation in guinea-pig pulmonary arteries. Br J Pharmacol 107:861–866

    PubMed  CAS  Google Scholar 

  8. Villar I, Francis S, Webb A, Hobbs A, Ahluwalia A (2006) Novel aspects of endothelium-dependent regulation of vascular tone. Kidney Int 70:840–853

    PubMed  CAS  Google Scholar 

  9. Davies PF (2008) Endothelial transcriptome profiles in vivo in ­complex arterial flow fields. Ann Biomed Eng 36:563–570

    PubMed  Google Scholar 

  10. Cooke JP, Rossitch E Jr, Andon NA, Loscalzo J, Dzau VJ (1991) Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator. J Clin Invest 88:1663–1671

    PubMed  CAS  Google Scholar 

  11. Oishi P, Azakie A, Harmon C, Fitzgerald RK, Grobe A, Xu J, Hendricks-Munoz K, Black SM, Fineman JR (2006) Nitric oxide-endothelin-1 interactions after surgically induced acute increases in pulmonary blood flow in intact lambs. Am J Physiol Heart Circ Physiol 290:H1922–H1932

    PubMed  CAS  Google Scholar 

  12. Webb G, Gatzoulis M (2006) Atrial septal defects in the adult: recent progress and overview. Circulation 114:1645–1653

    PubMed  Google Scholar 

  13. Steele P, Fuster V, Cohen M, Ritter D, McGoon D (1987) Isolated atrial septal defect with pulmonary vascular obstructive disease – long-term follow-up and prediction of outcome after surgical ­correction. Circulation 76:1037–1042

    PubMed  CAS  Google Scholar 

  14. Sakao S, Taraseviciene-Stewart L, Lee J, Wood K, Cool C, Voelkel N (2005) Initial apoptosis is followed by increased proliferation of apoptosis-resistant endothelial cells. FASEB J 19:1178–1180

    PubMed  CAS  Google Scholar 

  15. Barnes P, Liu S (1995) Regulation of pulmonary vascular tone. Pharmacol Rev 47:87–131

    PubMed  CAS  Google Scholar 

  16. Brashers VL, Peach MJ, Rose CE Jr (1988) Augmentation of hypoxic pulmonary vasoconstriction in the isolated perfused rat lung by in vitro antagonists of endothelium-dependent relaxation. J Clin Invest 82:1495–1502

    PubMed  CAS  Google Scholar 

  17. Archer SL, Tolins JP, Raij L, Weir EK (1989) Hypoxic pulmonary vasoconstriction is enhanced by inhibition of the synthesis of an endothelium derived relaxing factor. Biochem Biophys Res Commun 164:1198–1205

    PubMed  CAS  Google Scholar 

  18. Mazmanian GM, Baudet B, Brink C, Cerrina J, Kirkiacharian S, Weiss M (1989) Methylene blue potentiates vascular reactivity in isolated rat lungs. J Appl Physiol 66:1040–1045

    PubMed  CAS  Google Scholar 

  19. Ogata M, Ohe M, Katayose D, Takishima T (1992) Modulatory role of EDRF in hypoxic contraction of isolated porcine pulmonary arteries. Am J Physiol 262:H691–H697

    PubMed  CAS  Google Scholar 

  20. Voelkel NF, Gerber JG, McMurtry IF, Nies AS, Reeves JT (1981) Release of vasodilator prostaglandin, PGI2, from isolated rat lung during vasoconstriction. Circ Res 48:207–213

    PubMed  CAS  Google Scholar 

  21. Weir EK, McMurtry IF, Tucker A, Reeves JT, Grover RF (1976) Prostaglandin synthetase inhibitors do not decrease hypoxic ­pulmonary vasoconstriction. J Appl Physiol 41:714–718

    PubMed  CAS  Google Scholar 

  22. Sprague RS, Stephenson AH, Lonigro AJ (1984) Prostaglandin I2 supports blood flow to hypoxic alveoli in anesthetized dogs. J Appl Physiol 56:1246–1251

    PubMed  CAS  Google Scholar 

  23. Furchgott R, Zawadzki J (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376

    PubMed  CAS  Google Scholar 

  24. Graser T, Vanhoutte PM (1991) Hypoxic contraction of canine coronary arteries: role of endothelium and cGMP. Am J Physiol 261:H1769–H1777

    PubMed  CAS  Google Scholar 

  25. De Mey JG, Vanhoutte PM (1982) Heterogeneous behavior of the canine arterial and venous wall. Importance of the endothelium. Circ Res 51:439–447

    PubMed  Google Scholar 

  26. Stenmark KR, Fagan KA, Frid MG (2006) Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res 99:675–691

    PubMed  CAS  Google Scholar 

  27. Badesch DB, Orton EC, Zapp LM, Westcott JY, Hester J, Voelkel NF, Stenmark KR (1989) Decreased arterial wall prostaglandin production in neonatal calves with severe chronic pulmonary hypertension. Am J Respir Cell Mol Biol 1:489–498

    PubMed  CAS  Google Scholar 

  28. Faller DV (1999) Endothelial cell responses to hypoxic stress. Clin Exp Pharmacol Physiol 26:74–84

    PubMed  CAS  Google Scholar 

  29. Coggins M, Bloch K (2007) Nitric oxide in the pulmonary vasculature. Arterioscler Thromb Vasc Biol 27:1877–1885

    PubMed  CAS  Google Scholar 

  30. Dudzinski D, Igarashi J, Greif D, Michel T (2006) The regulation and pharmacology of endothelial nitric oxide synthase. Annu Rev Pharmacol Toxicol 46:235–276

    PubMed  CAS  Google Scholar 

  31. Fagan K, Tyler R, Sato K, Fouty B, Morris KJ, Huang P, McMurtry I, Rodman D (1999) Relative contributions of endothelial, inducible, and neuronal NOS to tone in the murine pulmonary circulation. Am J Physiol 277:L472–L478

    PubMed  CAS  Google Scholar 

  32. Stuehr D, Santolini J, Wang Z, Wei C, Adak S (2004) Update on mechanism and catalytic regulation in the NO synthases. J Biol Chem 279:36167–36170

    PubMed  CAS  Google Scholar 

  33. Khoo J, Nicoli T, Alp N, Fullerton J, Flint J, Channon K (2004) Congenic mapping and genotyping of the tetrahydrobiopterin-deficient hph-1 mouse. Mol Genet Metab 82:251–254

    PubMed  CAS  Google Scholar 

  34. Friebe A, Koesling D (2003) Regulation of nitric oxide-sensitive guanylyl cyclase. Circ Res 93:96–105

    PubMed  CAS  Google Scholar 

  35. Ballou D, Zhao Y, Brandish P, Marletta M (2002) Revisiting the kinetics of nitric oxide (NO) binding to soluble guanylate cyclase: the simple NO-binding model is incorrect. Proc Natl Acad Sci U S A 99:12097–12121

    PubMed  CAS  Google Scholar 

  36. Sauzeau V, Le Jeune H, Cario-Toumaniantz C, Smolenski A, Lohmann S, Bertoglio J, Chardin P, Pacaud P, Loirand G (2000) Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle. J Biol Chem 275:21722–21729

    PubMed  CAS  Google Scholar 

  37. Rybalkin S, Yan C, Bornfeldt K, Beavo J (2003) Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res 93:280–291

    PubMed  CAS  Google Scholar 

  38. Rabe K, Tenor H, Dent G, Schudt C, Nakashima M, Magnussen H (1994) Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors. Am J Physiol 266:L536–L543

    PubMed  CAS  Google Scholar 

  39. Stamler J, Simon D, Jaraki O, Osborne J, Francis S, Mullins M, Singel D, Loscalzo J (1992) S-nitrosylation of tissue-type plasminogen activator confers vasodilatory and antiplatelet properties on the enzyme. Proc Natl Acad Sci U S A 89:8087–8091

    PubMed  CAS  Google Scholar 

  40. Shiva S, Wang X, Ringwood L, Xu X, Yuditskaya S, Annavajjhala V, Miyajima H, Hogg N, Harris Z, Gladwin M (2006) Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis. Nat Chem Biol 2:486–493

    PubMed  CAS  Google Scholar 

  41. Kim-Shapiro D, Schechter A, Gladwin M (2006) Unraveling the reactions of nitric oxide, nitrite, and hemoglobin in physiology and therapeutics. Arterioscler Thromb Vasc Biol 26:697–705

    PubMed  CAS  Google Scholar 

  42. Singel D, Stamler J (2005) Chemical physiology of blood flow regulation by red blood cells: the role of nitric oxide and S-nitrosohemoglobin. Annu Rev Physiol 67:99–145

    PubMed  CAS  Google Scholar 

  43. Khoo J, Zhao L, Alp N, Bendall J, Nicoli T, Rockett K, Wilkins M, Channon K (2005) Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension. Circulation 111:2126–2133

    PubMed  CAS  Google Scholar 

  44. Shimokawa H, Takeshita A (2005) Rho-kinase is an important therapeutic target in cardiovascular medicine. Arterioscler Thromb Vasc Biol 25:1767–1775

    PubMed  CAS  Google Scholar 

  45. Nagaoka T, Morio Y, Casanova N, Bauer N, Gebb S, McMurtry I, Oka M (2004) Rho/Rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 287:L665–L672

    PubMed  CAS  Google Scholar 

  46. Oka M, Homma N, Taraseviciene-Stewart L, Morris K, Kraskauskas D, Burns N, Voelkel N, McMurtry I (2007) Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats. Circ Res 100:923–929

    PubMed  CAS  Google Scholar 

  47. Fagan K, Oka M, Bauer N, Gebb S, Ivy D, Morris K, McMurtry I (2004) Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase. Am J Physiol Lung Cell Mol Physiol 287:L656–L664

    PubMed  CAS  Google Scholar 

  48. Fukumoto Y, Matoba T, Ito A, Tanaka H, Kishi T, Hayashidani S, Abe K, Takeshita A, Shimokawa H (2005) Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart 91:391–392

    PubMed  CAS  Google Scholar 

  49. Nishimura T, Faul J, Berry G, Vaszar L, Qiu D, Pearl R, Kao P (2002) Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am J Respir Crit Care Med 166:1403–1408

    PubMed  Google Scholar 

  50. Robb G, Carson A, Tai S, Fish J, Singh S, Yamada T, Scherer S, Nakabayashi K, Marsden P (2004) Post-transcriptional regulation of endothelial nitric-oxide synthase by an overlapping antisense mRNA transcript. J Biol Chem 279:37982–37996

    PubMed  CAS  Google Scholar 

  51. Li X, Everson W, Smart E (2005) Caveolae, lipid rafts, and vascular disease. Trends Cardiovasc Med 15:92–96

    PubMed  CAS  Google Scholar 

  52. Gonzalez E, Kou R, Lin A, Golan D, Michel T (2002) Subcellular targeting and agonist-induced site-specific phosphorylation of endothelial nitric-oxide synthase. J Biol Chem 277:39554–39560

    PubMed  CAS  Google Scholar 

  53. Yeh D, Duncan J, Yamashita S, Michel T (1999) Depalmitoylation of endothelial nitric-oxide synthase by acyl-protein thioesterase 1 is potentiated by Ca2+-calmodulin. J Biol Chem 274:33148–33154

    PubMed  CAS  Google Scholar 

  54. Achcar R, Demura Y, Rai P, Taraseviciene-Stewart L, Kasper M, Voelkel N, Cool C (2006) Loss of caveolin and heme oxygenase expression in severe pulmonary hypertension. Chest 129:696–705

    PubMed  CAS  Google Scholar 

  55. Zhao Y, Liu Y, Stan R, Fan L, Gu Y, Dalton N, Chu P, Peterson K, Ross J, Chien K (2002) Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice. Proc Natl Acad Sci U S A 99:11375–11380

    PubMed  CAS  Google Scholar 

  56. Cooke J (2000) Does ADMA cause endothelial dysfunction? Arterioscler Thromb Vasc Biol 20:2032–2037

    PubMed  CAS  Google Scholar 

  57. Millatt L, Whitley G, Li D, Leiper J, Siragy H, Carey R, Johns R (2003) Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia-induced pulmonary hypertension. Circulation 108:1493–1498

    PubMed  CAS  Google Scholar 

  58. 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 N, Vallance P (2007) Disruption of methylarginine metabolism impairs vascular homeostasis. Nat Med 13:198–203

    PubMed  CAS  Google Scholar 

  59. Kielstein J, Bode-Böger S, Hesse G, Martens-Lobenhoffer J, Takacs A, Fliser D, Hoeper M (2005) Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 25:1414–1418

    PubMed  CAS  Google Scholar 

  60. Greif D, Sacks D, Michel T (2004) Calmodulin phosphorylation and modulation of endothelial nitric oxide synthase catalysis. Proc Natl Acad Sci U S A 101:1165–1170

    PubMed  CAS  Google Scholar 

  61. Michel J, Feron O, Sase K, Prabhakar P, Michel T (1997) Caveolin versus calmodulin. Counterbalancing allosteric modulators of endothelial nitric oxide synthase. J Biol Chem 272:25907–25912

    PubMed  CAS  Google Scholar 

  62. Bauer P, Fulton D, Boo Y, Sorescu G, Kemp B, Jo H, Sessa W (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 278:14841–14849

    PubMed  CAS  Google Scholar 

  63. Boo Y, Hwang J, Sykes M, Michell B, Kemp B, Lum H, Jo H (2002) Shear stress stimulates phosphorylation of eNOS at Ser(635) by a protein kinase A-dependent mechanism. Am J Physiol Heart Circ Physiol 283:H1819–H1828

    PubMed  CAS  Google Scholar 

  64. Michell B, Harris M, Chen Z, Ju H, Venema V, Blackstone M, Huang W, Venema R, Kemp B (2002) Identification of regulatory sites of phosphorylation of the bovine endothelial nitric-oxide ­synthase at serine 617 and serine 635. J Biol Chem 277:42344–42351

    PubMed  CAS  Google Scholar 

  65. Fleming I, Fisslthaler B, Dimmeler S, Kemp B, Busse R (2001) Phosphorylation of Thr495 regulates Ca2+/calmodulin-dependent endothelial nitric oxide synthase activity. Circ Res 88:E68–E75

    PubMed  CAS  Google Scholar 

  66. Ravi K, Brennan L, Levic S, Ross P, Black S (2004) S-nitrosylation of endothelial nitric oxide synthase is associated with monomerization and decreased enzyme activity. Proc Natl Acad Sci U S A 101:2619–2624

    PubMed  CAS  Google Scholar 

  67. Mombouli JV, Vanhoutte PM (1995) Kinins and endothelial ­control of vascular smooth muscle. Annu Rev Pharmacol Toxicol 35:679–705

    PubMed  CAS  Google Scholar 

  68. Skidgel RA (1992) Bradykinin-degrading enzymes: structure, function, distribution, and potential roles in cardiovascular pharmacology. J Cardiovasc Pharmacol 20:S4–S9

    PubMed  CAS  Google Scholar 

  69. Moncada S, Palmer R, Higgs E (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109–142

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  71. Isshiki M, Ando J, Korenaga R, Kogo H, Fujimoto T, Fujita T, Kamiya A (1998) Endothelial Ca2+ waves preferentially originate at specific loci in caveolin-rich cell edges. Proc Natl Acad Sci U S A 95:5009–5014

    PubMed  CAS  Google Scholar 

  72. Ming XF, Viswambharan H, Barandier C, Ruffieux J, Kaibuchi K, Rusconi S, Yang Z (2002) Rho GTPase/Rho kinase negatively regulates endothelial nitric oxide synthase phosphorylation through the inhibition of protein kinase B/Akt in human endothelial cells. Mol Cell Biol 22:8467–8477

    PubMed  CAS  Google Scholar 

  73. Eto M, Barandiér C, Rathgeb L, Kozai T, Joch H, Yang Z, Lüscher T (2001) Thrombin suppresses endothelial nitric oxide synthase and upregulates endothelin-converting enzyme-1 expression by distinct pathways: role of Rho/ROCK and mitogen-activated ­protein kinase. Circ Res 89:583–590

    PubMed  CAS  Google Scholar 

  74. Olivera A, Spiegel S (1993) Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature 365:557–560

    PubMed  CAS  Google Scholar 

  75. Muraki K, Imaizumi Y (2001) A novel function of sphingosine-1-phosphate to activate a non-selective cation channel in human endothelial cells. J Physiol 537:431–441

    PubMed  CAS  Google Scholar 

  76. Petrova TV, Makinen T, Alitalo K (1999) Signaling via vascular endothelial growth factor receptors. Exp Cell Res 253:117–130

    PubMed  CAS  Google Scholar 

  77. Ku DD, Zaleski JK, Liu S, Brock TA (1993) Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries. Am J Physiol Heart Circ Physiol 265:H586–H592

    CAS  Google Scholar 

  78. Kou R, Greif D, Michel T (2002) Dephosphorylation of endothelial nitric-oxide synthase by vascular endothelial growth factor. Implications for the vascular responses to cyclosporin A. J Biol Chem 277:29669–29673

    PubMed  CAS  Google Scholar 

  79. He H, Venema VJ, Gu X, Venema RC, Marrero MB, Caldwell RB (1999) Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR ­activation of c-Src. J Biol Chem 274:25130–25135

    PubMed  CAS  Google Scholar 

  80. Erwin P, Lin A, Golan D, Michel T (2005) Receptor-regulated dynamic S-nitrosylation of endothelial nitric-oxide synthase in ­vascular endothelial cells. J Biol Chem 280:19888–19894

    PubMed  CAS  Google Scholar 

  81. Montagnani M, Chen H, Barr VA, Quon MJ (2001) Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser1179. J Biol Chem 276:30392–30398

    PubMed  CAS  Google Scholar 

  82. 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 108:1341–1348

    PubMed  CAS  Google Scholar 

  83. Guetta V, Quyyumi AA, Prasad A, Panza JA, Waclawiw M, Cannon RO III (1997) The role of nitric oxide in coronary vascular effects of estrogen in postmenopausal women. Circulation 96:2795–2801

    PubMed  CAS  Google Scholar 

  84. Caulin-Glaser T, Garcia-Cardeña G, Sarrel P, Sessa WC, Bender JR (1997) 17β-Estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization. Circ Res 81:885–892

    PubMed  CAS  Google Scholar 

  85. Lantin-Hermoso RL, Rosenfeld CR, Yuhanna IS, German Z, Chen Z, Shaul PW (1997) Estrogen acutely stimulates nitric oxide ­synthase activity in fetal pulmonary artery endothelium. Am J Physiol 273:L119–L126

    PubMed  CAS  Google Scholar 

  86. Yamamoto K, Korenaga R, Kamiya A, Ando J (2000) Fluid shear stress activates Ca2+ influx into human endothelial cells via P2X4 purinoceptors. Circ Res 87:385–391

    PubMed  CAS  Google Scholar 

  87. Gudi S, Nolan JP, Frangos JA (1998) Modulation of GTPase ­activity of G proteins by fluid shear stress and phospholipid ­composition. Proc Natl Acad Sci U S A 95:2515–2519

    PubMed  CAS  Google Scholar 

  88. Botney M (1999) Role of hemodynamics in pulmonary vascular remodeling: implications for primary pulmonary hypertension. Am J Respir Crit Care Med 159:361–364

    PubMed  CAS  Google Scholar 

  89. Cool C, Groshong S, Oakey J, Voelkel N (2005) Pulmonary hypertension: cellular and molecular mechanisms. Chest 128:565S–571S

    PubMed  CAS  Google Scholar 

  90. Ghorishi Z, Milstein J, Poulain F, Moon-Grady A, Tacy T, Bennett S, Fineman J, Eldridge M (2007) Shear stress paradigm for perinatal fractal arterial network remodeling in lambs with pulmonary hypertension and increased pulmonary blood flow. Am J Physiol Heart Circ Physiol 292:H3006–H3018

    PubMed  CAS  Google Scholar 

  91. Liu R, Evgenov O, Ichinose F (2005) NOS3 deficiency augments hypoxic pulmonary vasoconstriction and enhances systemic oxygenation during one-lung ventilation in mice. J Appl Physiol 98:748–752

    PubMed  CAS  Google Scholar 

  92. Shaul P, North A, Brannon T, Ujiie K, Wells L, Nisen P, Lowenstein C, Snyder S, Star R (1995) Prolonged in vivo hypoxia enhances nitric oxide synthase type I and type III gene expression in adult rat lung. Am J Respir Cell Mol Biol 13:167–174

    PubMed  CAS  Google Scholar 

  93. Steudel W, Ichinose F, Huang P, Hurford W, Jones R, Bevan J, Fishman M, Zapol W (1997) Pulmonary vasoconstriction and hypertension in mice with targeted disruption of the endothelial nitric oxide synthase (NOS 3) gene. Circ Res 81:34–41

    PubMed  CAS  Google Scholar 

  94. Fagan K, Fouty B, Tyler R, Morris K, Hepler L, Sato K, LeCras T, Abman S, Weinberger H, Huang P, McMurtry I, Rodman D (1999) The pulmonary circulation of homozygous or heterozygous eNOS-null mice is hyperresponsive to mild hypoxia. J Clin Invest 103:291–299

    PubMed  CAS  Google Scholar 

  95. Quinlan T, Li D, Laubach V, Shesely E, Zhou N, Johns R (2000) eNOS-deficient mice show reduced pulmonary vascular proliferation and remodeling to chronic hypoxia. Am J Physiol Lung Cell Mol Physiol 279:L641–L650

    PubMed  CAS  Google Scholar 

  96. Murata T, Sato K, Hori M, Ozaki H, Karaki H (2002) Decreased endothelial nitric-oxide synthase (eNOS) activity resulting from abnormal interaction between eNOS and its regulatory proteins in hypoxia-induced pulmonary hypertension. J Biol Chem 277:44085–44092

    PubMed  CAS  Google Scholar 

  97. Janssens S, Bloch K, Nong Z, Gerard R, Zoldhelyi P, Collen D (1996) Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary ­vasoconstriction in rats. J Clin Invest 98:317–324

    PubMed  CAS  Google Scholar 

  98. Champion H, Bivalacqua T, Greenberg S, Giles T, Hyman A, Kadowitz P (2002) Adenoviral gene transfer of endothelial nitric-oxide synthase (eNOS) partially restores normal pulmonary arterial pressure in eNOS-deficient mice. Proc Natl Acad Sci U S A 99:13248–13253

    PubMed  CAS  Google Scholar 

  99. Zhao Y, Courtman D, Deng Y, Kugathasan L, Zhang Q, Stewart D (2005) Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res 96:442–450

    PubMed  CAS  Google Scholar 

  100. Kanki-Horimoto S, Horimoto H, Mieno S, Kishida K, Watanabe F, Furuya E, Katsumata T (2006) Implantation of mesenchymal stem cells overexpressing endothelial nitric oxide synthase improves right ventricular impairments caused by pulmonary hypertension. Circulation 114:I181–I185

    PubMed  Google Scholar 

  101. Girgis R, Li D, Zhan X, Garcia J, Tuder R, Hassoun P, Johns R (2003) Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Circ Physiol 285:H938–H945

    PubMed  CAS  Google Scholar 

  102. Murata T, Kinoshita K, Hori M, Kuwahara M, Tsubone H, Karaki H, Ozaki H (2005) Statin protects endothelial nitric oxide synthase activity in hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol 25:2335–2342

    PubMed  CAS  Google Scholar 

  103. Hemnes AR, Champion H (2006) Sildenafil, a PDE5 inhibitor, in the treatment of pulmonary hypertension. Expert Rev Cardiovasc Ther 4:293–300

    PubMed  CAS  Google Scholar 

  104. Chan S, Loscalzo J (2008) Pathogenic mechanisms of pulmonary arterial hypertension. J Mol Cell Cardiol 44:14–30

    PubMed  CAS  Google Scholar 

  105. Balsinde J, Winstead M, Dennis E (2002) Phospholipase A2 ­regulation of arachidonic acid mobilization. FEBS Lett 531:2–6

    PubMed  CAS  Google Scholar 

  106. Birks EK, Bousamra M, Presberg K, Marsh JA, Effros RM, Jacobs ER (1997) Human pulmonary arteries dilate to 20-HETE, an endogenous eicosanoid of lung tissue. Am J Physiol 272:L823–L829

    PubMed  CAS  Google Scholar 

  107. Bogatcheva N, Sergeeva M, Dudek S, Verin A (2005) Arachidonic acid cascade in endothelial pathobiology. Microvasc Res 69:107–127

    PubMed  CAS  Google Scholar 

  108. Tsuboi K, Sugimoto Y, Ichikawa A (2002) Prostanoid receptor subtypes. Prostaglandins Other Lipid Mediat 68–69:535–556

    PubMed  Google Scholar 

  109. Breyer RM, Bagdassarian CK, Myers SA, Breyer MD (2001) Prostanoid receptors: subtypes and signaling. Ann Rev Pharmacol Toxicol 41:661–690

    CAS  Google Scholar 

  110. Gerber J, Voelkel N, Nies A, McMurtry I, Reeves J (1980) Moderation of hypoxic vasoconstriction by infused arachidonic acid: role of PGI2. J Appl Physiol 49:107–112

    PubMed  CAS  Google Scholar 

  111. Negishi M, Katoh H (2002) Cyclopentenone prostaglandin receptors. Prostaglandins Other Lipid Mediat 68–69:611–617

    PubMed  Google Scholar 

  112. Strauss W, Edelman J (2007) Prostanoid therapy for pulmonary arterial hypertension. Clin Chest Med 28:127–142, ix

    Google Scholar 

  113. Spencer A, Woods J, Arakawa T, Singer I, Smith W (1998) Subcellular localization of prostaglandin endoperoxide H synthases-1 and -2 by immunoelectron microscopy. J Biol Chem 273:9886–9893

    PubMed  CAS  Google Scholar 

  114. Morita I (2002) Distinct functions of COX-1 and COX-2. Prostaglandins Other Lipid Mediat 68–69:165–175

    PubMed  Google Scholar 

  115. DeWitt D, Day J, Sonnenburg W, Smith W (1983) Concentrations of prostaglandin endoperoxide synthase and prostaglandin I2 synthase in the endothelium and smooth muscle of bovine aorta. J Clin Invest 72:1882–1888

    PubMed  CAS  Google Scholar 

  116. Guan Z, Buckman S, Pentland A, Templeton D, Morrison A (1998) Induction of cyclooxygenase-2 by the activated MEKK1 SEK1/MKK4 p38 mitogen-activated protein kinase pathway. J Biol Chem 273:12901–12908

    PubMed  CAS  Google Scholar 

  117. Toratani A, Sawada S, Kono Y, Higaki T, Imamura H, Tada Y, Yamasaki S, Sato T, Komatsu S, Akamatsu N, Tamagaki T, Nakagawa K, Tsuji H, Nakagawa M (1999) Interleukin-1 stimulated prostacyclin release by increasing gene transcription of ­prostaglandin H synthase and phospholipase A2 in human vascular endothelial cells. J Cardiovasc Pharmacol 33:843–851

    PubMed  CAS  Google Scholar 

  118. Cockerill G, Saklatvala J, Ridley S, Yarwood H, Miller N, Oral B, Nithyanathan S, Taylor G, Haskard D (1999) High-density lipoproteins differentially modulate cytokine-induced expression of E-selectin and cyclooxygenase-2. Arterioscler Thromb Vasc Biol 19:910–917

    PubMed  CAS  Google Scholar 

  119. Fang X, Moore A, Nwankwo J, Weintraub L, Oberley W, Snyder D, Spector A (2000) Induction of cyclooxygenase-2 by overexpression of the human catalase gene in cerebral microvascular endothelial cells. J Neurochem 75:614–623

    PubMed  CAS  Google Scholar 

  120. Rikitake Y, Hirata K, Kawashima S, Takeuchi S, Shimokawa Y, Kojima Y, Inoue N, Yokoyama M (2001) Signaling mechanism underlying COX-2 induction by lysophosphatidylcholine. Biochem Biophys Res Commun 281:1291–1297

    PubMed  CAS  Google Scholar 

  121. Hirai K, Ezumi Y, Nishida E, Uchiyama T, Takayama H (1999) Comparative study of vanadate- and phorbol ester-induced cyclooxygenase-2 expression in human endothelial cells. Thromb Haemost 82:1545–1552

    PubMed  CAS  Google Scholar 

  122. Ji Y, Xu Q, Schmedtje J (1998) Hypoxia induces high-mobility-group protein I(Y) and transcription of the cyclooxygenase-2 gene in human vascular endothelium. Circ Res 83:295–304

    PubMed  CAS  Google Scholar 

  123. Samokovlisky A, Rimon G, Danon A (1999) Differential regulation of cyclooxygenase isoenzymes by cAMP-elevating agents. Eur J Pharmacol 378:203–211

    PubMed  CAS  Google Scholar 

  124. Elalamy I, Said F, Singer M, Couetil J, Hatmi M (2000) Inhibition by extracellular cAMP of phorbol 12-myristate 13-acetate-induced prostaglandin H synthase-2 expression in human pulmonary microvascular endothelial cells. Involvement of an ecto-protein kinase A activity. J Biol Chem 275:13662–13667

    PubMed  CAS  Google Scholar 

  125. Manalo D, Rowan A, Lavoie T, Natarajan L, Kelly B, Ye S, Garcia J, Semenza G (2005) Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105:659–669

    PubMed  CAS  Google Scholar 

  126. Marx N, Bourcier T, Sukhova G, Libby P, Plutzky J (1999) PPARγ activation in human endothelial cells increases plasminogen activator inhibitor type-1 expression: PPARγ as a potential mediator in vascular disease. Atheroscler Thromb Vasc Biol 19:546–551

    CAS  Google Scholar 

  127. Inoue H, Tanabe T, Umesono K (2000) Feedback control of cyclooxygenase-2 expression through PPARγ. J Biol Chem 275:28028–28032

    PubMed  CAS  Google Scholar 

  128. Staels B, Koenig W, Habib A, Merval R, Lebret M, Torra I, Delerive P, Fadel A, Chinetti G, Fruchart J, Najib J, Maclouf J, Tedgui A (1998) Activation of human aortic smooth-muscle cells is inhibited by PPARα but not by PPARγ activators. Nature 393:790–793

    PubMed  CAS  Google Scholar 

  129. Meade E, McIntyre T, Zimmerman G, Prescott S (1999) Peroxisome proliferators enhance cyclooxygenase-2 expression in epithelial cells. J Biol Chem 274:8328–8334

    PubMed  CAS  Google Scholar 

  130. Smith W, DeWitt D, Garavito R (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69:145–182

    PubMed  CAS  Google Scholar 

  131. Davidge S, Pitt B, McLaughlin M, Roberts J, Johnson B (1999) Biphasic stimulation of prostacyclin by endogenous nitric oxide (NO) in endothelial cells transfected with inducible NO synthase. Gen Pharmacol 33:383–387

    PubMed  CAS  Google Scholar 

  132. Wolin M (2000) Interactions of oxidants with vascular signaling systems. Arterioscler Thromb Vasc Biol 20:1430–1442

    PubMed  CAS  Google Scholar 

  133. Cheng Y, Austin S, Rocca B, Koller B, Coffman T, Grosser T, Lawson J, FitzGerald G (2002) Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 296:539–541

    PubMed  CAS  Google Scholar 

  134. Hickey K, Rubanyi G, Paul R, Highsmith R (1985) Characterization of a coronary vasoconstrictor produced by cultured endothelial cells. Am J Physiol 248:C550–C556

    PubMed  CAS  Google Scholar 

  135. Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, Masaki T (1989) The human endothelin family: three ­structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci U S A 86:2863–2867

    PubMed  CAS  Google Scholar 

  136. Masaki T (2004) Historical review: endothelin. Trends Pharmacol Sci 25:219–224

    PubMed  CAS  Google Scholar 

  137. Emoto N, Yanagisawa M (1995) Endothelin-converting enzyme-2 is a membrane-bound, phosphoramidon-sensitive metalloprotease with acidic pH optimum. J Biol Chem 270:15262–15268

    PubMed  CAS  Google Scholar 

  138. Yanagisawa H, Hammer R, Richardson J, Emoto N, Williams S, Takeda S, Clouthier D, Yanagisawa M (2000) Disruption of ECE-1 and ECE-2 reveals a role for endothelin-converting enzyme-2 in murine cardiac development. J Clin Invest 105:1373–1382

    PubMed  CAS  Google Scholar 

  139. Haynes W, Ferro C, O’Kane K, Somerville D, Lomax C, Webb D (1996) Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans. Circulation 93:1860–1870

    PubMed  CAS  Google Scholar 

  140. Masaki T, Miwa S, Sawamura T, Ninomiya H, Okamoto Y (1999) Subcellular mechanisms of endothelin action in vascular system. Eur J Pharmacol 375:133–138

    PubMed  CAS  Google Scholar 

  141. Miwa S, Iwamuro Y, Zhang X, Inoki T, Okamoto Y, Okazawa M, Masaki T (1999) Ca2+ entry channels in rat thoracic aortic smooth muscle cells activated by endothelin-1. Jpn J Pharmacol 80:281–288

    PubMed  CAS  Google Scholar 

  142. Douglas S, Meek T, Ohlstein E (1994) Novel receptor antagonists welcome a new era in endothelin biology. Trends Pharmacol Sci 15:313–316

    PubMed  CAS  Google Scholar 

  143. Hasunuma K, Rodman DM, O’Brien RF, McMurtry IF (1990) Endothelin 1 causes pulmonary vasodilation in rats. Am J Physiol 259:H48–H54

    PubMed  CAS  Google Scholar 

  144. Jeffery T, Morrell N (2002) Molecular and cellular basis of ­pulmonary vascular remodeling in pulmonary hypertension. Prog Cardiovasc Dis 45:173–202

    PubMed  CAS  Google Scholar 

  145. Touyz R, Schiffrin E (2003) Role of endothelin in human ­hypertension. Can J Physiol Pharmacol 81:533–541

    PubMed  CAS  Google Scholar 

  146. Hu J, Discher D, Bishopric N, Webster K (1998) Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand. Biochem Biophys Res Commun 245:894–899

    PubMed  CAS  Google Scholar 

  147. Bloch K, Friedrich S, Lee M, Eddy R, Shows T, Quertermous T (1989) Structural organization and chromosomal assignment of the gene encoding endothelin. J Biol Chem 264:10851–10857

    PubMed  CAS  Google Scholar 

  148. Inoue A, Yanagisawa M, Takuwa Y, Mitsui Y, Kobayashi M, Masaki T (1989) The human preproendothelin-1 gene. Complete nucleotide sequence and regulation of expression. J Biol Chem 264:14954–14959

    PubMed  CAS  Google Scholar 

  149. Mawji I, Marsden P (2003) Perturbations in paracrine control of the circulation: role of the endothelial-derived vasomediators, endothelin-1 and nitric oxide. Microsc Res Tech 60:46–58

    PubMed  CAS  Google Scholar 

  150. Boulanger C, Lüscher T (1990) Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide. J Clin Invest 85:587–590

    PubMed  CAS  Google Scholar 

  151. Kourembanas S, McQuillan L, Leung G, Faller D (1993) Nitric oxide regulates the expression of vasoconstrictors and growth ­factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest 92:99–104

    PubMed  CAS  Google Scholar 

  152. Kuchan M, Frangos J (1993) Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells. Am J Physiol 264:H150–H156

    PubMed  CAS  Google Scholar 

  153. Marsen T, Egink G, Suckau G, Baldamus C (1999) Tyrosine-kinase-dependent regulation of the nitric oxide synthase gene by endothelin-1 in human endothelial cells. Pflugers Arch Eur J Physiol 438:538–544

    CAS  Google Scholar 

  154. Kurihara Y, Kurihara H, Suzuki H, Kodama T, Maemura K, Nagai R, Oda H, Kuwaki T, Cao W, Kamada N, Jishage K, Ouchi Y, Azuma S, Toyoda Y, Ishikawa T, Kumada M, Yazaki Y (1994) Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature 368:703–710

    PubMed  CAS  Google Scholar 

  155. Ding H, Kubes P, Triggle C (2000) Potassium- and acetylcholine-induced vasorelaxation in mice lacking endothelial nitric oxide synthase. Br J Pharmacol 129:1194–1200

    PubMed  CAS  Google Scholar 

  156. Brandes R, Schmitz-Winnenthal F, Félétou M, Gödecke A, Huang P, Vanhoutte P, Fleming I, Busse R (2000) An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice. Proc Natl Acad Sci U S A 97:9747–9752

    PubMed  CAS  Google Scholar 

  157. Scotland RS, Madhani M, Chauhan S, Moncada S, Andresen J, Nilsson H, Hobbs AJ, Ahluwalia A (2005) Investigation of vascular responses in endothelial nitric oxide synthase/cyclooxygenase-1 double-knockout mice: key role for endothelium-derived hyperpolarizing factor in the regulation of blood pressure in vivo. Circulation 111:796–803

    PubMed  CAS  Google Scholar 

  158. Busse R, Edwards G, Félétou M, Fleming I, Vanhoutte P, Weston A (2002) EDHF: bringing the concepts together. Trends Pharmacol Sci 23:374–380

    PubMed  CAS  Google Scholar 

  159. Feletou M, Vanhoutte PM (2006) Endothelium-derived hyperpolarizing factor: where are we now? Arterioscler Thromb Vasc Biol 26:1215–1225

    PubMed  CAS  Google Scholar 

  160. Luckhoff A, Pohl U, Mulsch 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 95:189–196

    PubMed  CAS  Google Scholar 

  161. Johns A, Freay AD, Adams DJ, Lategan TW, Ryan US, van Breemen C (1988) Role of calcium in the activation of endothelial cells. J Cardiovasc Pharmacol 12:S119–S123

    PubMed  CAS  Google Scholar 

  162. Garland C, Plane F (1996) Relative importance of endothelium-derived hyperpolarizing factor for the relaxation of vascular smooth muscle in different arterial beds. In: Vanhoutte P (ed) Endothelium-derived hyperpolarizing factor. Harwood, Amsterdam, pp 173–179

    Google Scholar 

  163. Corriu C, Félétou M, Canet E, Vanhoutte P (1996) Endothelium-derived factors and hyperpolarization of the carotid artery of the guinea-pig. Br J Pharmacol 119:959–964

    PubMed  CAS  Google Scholar 

  164. Zygmunt PM, Edwards G, Weston AH, Larsson B, Hogestatt ED (1997) Involvement of voltage-dependent potassium channels in the EDHF-mediated relaxation of rat hepatic artery. Br J Pharmacol 121:141–149

    PubMed  CAS  Google Scholar 

  165. Fang X, Kaduce TL, Weintraub NL, Harmon S, Teesch LM, Morisseau C, Thompson DA, Hammock BD, Spector AA (2001) Pathways of epoxyeicosatrienoic acid metabolism in endothelial cells. Implications for the vascular effects of soluble epoxide hydrolase inhibition. J Biol Chem 276:14867–14874

    PubMed  CAS  Google Scholar 

  166. Campbell WB, Holmes BB, Falck JR, Capdevila JH, Gauthier KM (2006) Regulation of potassium channels in coronary smooth muscle by adenoviral expression of cytochrome P-450 epoxygenase. Am J Physiol Heart Circ Physiol 290:H64–H71

    PubMed  CAS  Google Scholar 

  167. Fleming I (2004) Cytochrome P450 epoxygenases as EDHF synthase(s). Pharmacol Res 49:525–533

    PubMed  CAS  Google Scholar 

  168. Gauthier KM, Falck JR, Reddy LM, Campbell WB (2004) 14, 15-EET analogs: characterization of structural requirements for agonist and antagonist activity in bovine coronary arteries. Pharmacol Res 49:515–524

    PubMed  CAS  Google Scholar 

  169. Popp R, Bauersachs J, Hecker M, Fleming I, Busse R (1996) A transferable, beta-naphthoflavone-inducible, hyperpolarizing factor is synthesized by native and cultured porcine coronary endothelial cells. J Physiol 497:699–709

    PubMed  CAS  Google Scholar 

  170. Campbell W, Gebremedhin D, Pratt P, Harder D (1996) Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ Res 78:415–423

    PubMed  CAS  Google Scholar 

  171. Honing M, Smits P, Morrison P, Rabelink T (2000) Bradykinin-induced vasodilation of human forearm resistance vessels is ­primarily mediated by endothelium-dependent hyperpolarization. Hypertension 35:1314–1318

    PubMed  CAS  Google Scholar 

  172. Taddei S, Versari D, Cipriano A, Ghiadoni L, Galetta F, Franzoni F, Magagna A, Virdis A, Salvetti A (2006) Identification of a ­cytochrome P450 2C9-derived endothelium-derived hyperpolarizing factor in essential hypertensive patients. J Am Coll Cardiol 48:508–515

    PubMed  CAS  Google Scholar 

  173. Widmann MD, Weintraub NL, Fudge JL, Brooks LA, Dellsperger KC (1998) Cytochrome P-450 pathway in acetylcholine-induced canine coronary microvascular vasodilation in vivo. Am J Physiol 274:H283–H289

    PubMed  CAS  Google Scholar 

  174. Tan JZ, Kaley G, Gurtner GH (1997) Nitric oxide and prostaglandins mediate vasodilation to 5,6-EET in rabbit lung. Adv Exp Med Biol 407:561–566

    PubMed  CAS  Google Scholar 

  175. Schwartzman M, Ferreri NR, Carroll MA, Songu-Mize E, McGiff JC (1985) Renal cytochrome P450-related arachidonate ­metabolite inhibits (Na++ K+)ATPase. Nature 314:620–622

    PubMed  CAS  Google Scholar 

  176. Zhu D, Bousamra M II, Zeldin DC, Falck JR, Townsley M, Harder DR, Roman RJ, Jacobs ER (2000) Epoxyeicosatrienoic acids ­constrict isolated pressurized rabbit pulmonary arteries. Am J Physiol Lung Cell Mol Physiol 278:L335–L343

    PubMed  CAS  Google Scholar 

  177. Stephenson AH, Sprague RS, Losapio JL, Lonigro AJ (2003) Differential effects of 5,6-EET on segmental pulmonary vasoactivity in the rabbit. Am J Physiol Heart Circ Physiol 284:H2153–H2161

    PubMed  CAS  Google Scholar 

  178. Losapio JL, Sprague RS, Lonigro AJ, Stephenson AH (2005) 5,6-EET-induced contraction of intralobar pulmonary arteries depends on the activation of Rho-kinase. J Appl Physiol 99:1391–1396

    PubMed  CAS  Google Scholar 

  179. Shimokawa H, Matoba T (2004) Hydrogen peroxide as an endothelium-derived hyperpolarizing factor. Pharmacol Res 49:543–549

    PubMed  CAS  Google Scholar 

  180. Beny JL, von der Weid PY (1991) Hydrogen peroxide: an endogenous smooth muscle cell hyperpolarizing factor. Biochem Biophys Res Commun 176:378–384

    PubMed  CAS  Google Scholar 

  181. Wei C, Hu S, Miller V, Burnett J (1994) Vascular actions of C-type natriuretic peptide in isolated porcine coronary arteries and ­coronary vascular smooth muscle cells. Biochem Biophys Res Commun 205:765–771

    PubMed  CAS  Google Scholar 

  182. Osher E, Weisinger G, Limor R, Tordjman K, Stern N (2006) The 5 lipoxygenase system in the vasculature: emerging role in health and disease. Mol Cell Endocrinol 252:201–206

    PubMed  CAS  Google Scholar 

  183. Hammarberg T, Provost P, Persson B, Radmark O (2000) The N-terminal domain of 5-lipoxygenase binds calcium and mediates calcium stimulation of enzyme activity. J Biol Chem 275:38787–38793

    PubMed  CAS  Google Scholar 

  184. Werz O, Klemm J, Samuelsson B, Radmark O (2000) 5-lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinases. Proc Natl Acad Sci U S A 97:5261–5266

    PubMed  CAS  Google Scholar 

  185. Werz O, Steinhilber D (1996) Selenium-dependent peroxidases suppress 5-lipoxygenase activity in B-lymphocytes and immature myeloid cells. The presence of peroxidase-insensitive 5-lipoxygenase activity in differentiated myeloid cells. Eur J Biochem 242:90–97

    PubMed  CAS  Google Scholar 

  186. Spanbroek R, Hildner M, Kohler A, Muller A, Zintl F, Kuhn H, Radmark O, Samuelsson B, Habenicht AJ (2001) IL-4 determines eicosanoid formation in dendritic cells by down-regulation of 5-lipoxygenase and up-regulation of 15-lipoxygenase 1 expression. Proc Natl Acad Sci U S A 98:5152–5157

    PubMed  CAS  Google Scholar 

  187. Stanke-Labesque F, Devillier P, Veitl S, Caron F, Cracowski JL, Bessard G (2001) Cysteinyl leukotrienes are involved in angiotensin II-induced contraction of aorta from spontaneously hypertensive rats. Cardiovasc Res 49:152–160

    PubMed  CAS  Google Scholar 

  188. Hardy G, Stanke-Labesque F, Peoc’h M, Hakim A, Devillier P, Caron F, Morel S, Faure P, Halimi S, Bessard G (2001) Cysteinyl leukotrienes modulate angiotensin II constrictor effects on aortas from streptozotocin-induced diabetic rats. Arterioscler Thromb Vasc Biol 21:1751–1758

    PubMed  CAS  Google Scholar 

  189. Lotzer K, Spanbroek R, Hildner M, Urbach A, Heller R, Bretschneider E, Galczenski H, Evans JF, Habenicht AJ (2003) Differential leukotriene receptor expression and calcium responses in endothelial cells and macrophages indicate 5-lipoxygenase-dependent circuits of inflammation and atherogenesis. Arterioscler Thromb Vasc Biol 23:e32–e36

    PubMed  Google Scholar 

  190. Berkowitz BA, Zabko-Potapovich B, Valocik R, Gleason JG (1984) Effects of the leukotrienes on the vasculature and blood pressure of different species. J Pharmacol Exp Ther 229:105–112

    PubMed  CAS  Google Scholar 

  191. Mazzetti L, Franchi-Micheli S, Nistri S, Quattrone S, Simone R, Ciuffi M, Zilletti L, Failli P (2003) The ACh-induced contraction in rat aortas is mediated by the Cys Lt1 receptor via intracellular calcium mobilization in smooth muscle cells. Br J Pharmacol 138:707–715

    PubMed  CAS  Google Scholar 

  192. Allen S, Dashwood M, Morrison K, Yacoub M (1998) Differential leukotriene constrictor responses in human atherosclerotic coronary arteries. Circulation 97:2406–2413

    PubMed  CAS  Google Scholar 

  193. Shastri S, McNeill J, Wilson T, Poduri R, Kaul C, Gopalakrishnan V (2001) Cysteinyl leukotrienes mediate enhanced vasoconstriction to angiotensin II but not endothelin-1 in SHR. Am J Physiol Heart Circ Physiol 281:H342–H349

    PubMed  CAS  Google Scholar 

  194. Yet S, Perrella M, Layne M, Hsieh C, Maemura K, Kobzik L, Wiesel P, Christou H, Kourembanas S, Lee M (1999) Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice. J Clin Invest 103:R23–R29

    PubMed  CAS  Google Scholar 

  195. Christou H, Morita T, Hsieh C, Koike H, Arkonac B, Perrella M, Kourembanas S (2000) Prevention of hypoxia-induced pulmonary hypertension by enhancement of endogenous heme oxygenase-1 in the rat. Circ Res 86:1224–1229

    PubMed  CAS  Google Scholar 

  196. Zuckerbraun B, Chin B, Wegiel B, Billiar T, Czsimadia E, Rao J, Shimoda L, Ifedigbo E, Kanno S, Otterbein L (2006) Carbon monoxide reverses established pulmonary hypertension. J Exp Med 203:2109–2119

    PubMed  CAS  Google Scholar 

  197. Chunyu Z, Junbao D, Dingfang B, Hui Y, Xiuying T, Chaoshu T (2003) The regulatory effect of hydrogen sulfide on hypoxic pulmonary hypertension in rats. Biochem Biophys Res Commun 302:810–816

    PubMed  Google Scholar 

  198. Li X, Du J, Ding Y, Jin H, Bu D, Tang X, Tang C (2006) Impact of hydrogen sulfide donor on experimental pulmonary hypertension induced by high pulmonary flow and endogenous carbon monoxide/heme oxygenase pathway. J Peking Univ Health Sci 38:135–139

    CAS  Google Scholar 

  199. Petkov V, Mosgoeller W, Ziesche R, Raderer M, Stiebellehner L, Vonbank K, Funk G, Hamilton G, Novotny C, Burian B, Block L (2003) Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest 111:1339–1346

    PubMed  CAS  Google Scholar 

  200. Said S, Hamidi S, Dickman K, Szema A, Lyubsky S, Lin R, Jiang Y, Chen J, Waschek J, Kort S (2007) Moderate pulmonary arterial hypertension in male mice lacking the vasoactive intestinal ­peptide gene. Circulation 115:1260–1268

    PubMed  CAS  Google Scholar 

  201. Söderman C, Eriksson L, Juhlin-Dannfelt A, Lundberg J, Broman L, Holmgren A (1993) Effect of vasoactive intestinal polypeptide (VIP) on pulmonary ventilation-perfusion relationships and central haemodynamics in healthy subjects. Clin Physiol 13:677–685

    PubMed  Google Scholar 

  202. Hall SM, Haworth SG (1986) Normal adaptation of pulmonary arterial intima to extrauterine life in the pig: ultrastructural studies. J Pathol 149:55–66

    PubMed  CAS  Google Scholar 

  203. Haworth SG, Hall SM, Chew M, Allen K (1987) Thinning of fetal pulmonary arterial wall and postnatal remodelling: ultrastructural studies on the respiratory unit arteries of the pig. Virchows Arch A Pathol Anat Histopathol 411:161–171

    PubMed  CAS  Google Scholar 

  204. Wallace KB, Bailie MD, Hook JB (1979) Development of ­angiotensin-converting enzyme in fetal rat lungs. Am J Physiol 236:R57–R60

    PubMed  CAS  Google Scholar 

  205. Moreau P, d’Uscio LV, Shaw S, Takase H, Barton M, Luscher TF (1997) Angiotensin II increases tissue endothelin and induces ­vascular hypertrophy: reversal by ETA-receptor antagonist. Circulation 96:1593–1597

    PubMed  CAS  Google Scholar 

  206. Hislop AA, Springall DR, Buttery LD, Pollock JS, Haworth SG (1995) Abundance of endothelial nitric oxide synthase in newborn intrapulmonary arteries. Arch Dis Child Fetal Neonatal Ed 73:F17–F21

    PubMed  CAS  Google Scholar 

  207. Noguchi Y, Hislop AA, Haworth SG (1997) Influence of hypoxia on endothelin-1 binding sites in neonatal porcine pulmonary ­vasculature. Am J Physiol 272:H669–H678

    PubMed  CAS  Google Scholar 

  208. Dawes GS (1966) Pulmonary circulation in the foetus and ­new-born. Br Med Bull 22:61–65

    PubMed  CAS  Google Scholar 

  209. Cassin S, Tod ML, Frisinger JE, Jordan JA, Philips JB (1979) Use of prostacyclin in persistent fetal circulation. Lancet 2:638

    PubMed  CAS  Google Scholar 

  210. Morin FC III, Egan EA, Ferguson W, Lundgren CE (1988) Development of pulmonary vascular response to oxygen. Am J Physiol 254:H542–H546

    PubMed  Google Scholar 

  211. Shaul PW, Afshar S, Gibson LL, Sherman TS, Kerecman JD, Grubb PH, Yoder BA, McCurnin DC (2002) Developmental changes in nitric oxide synthase isoform expression and nitric oxide production in fetal baboon lung. Am J Physiol Lung Cell Mol Physiol 283:L1192–L1199

    PubMed  CAS  Google Scholar 

  212. Han R, Babaei S, Robb M, Lee T, Ridsdale R, Ackerley C, Post M, Stewart D (2004) Defective lung vascular development and fatal respiratory distress in endothelial NO synthase-deficient mice: a model of alveolar capillary dysplasia? Circ Res 94:1115–1123

    PubMed  CAS  Google Scholar 

  213. Michalsky MP, Arca MJ, Groenman F, Hammond S, Tibboel D, Caniano DA (2005) Alveolar capillary dysplasia: a logical approach to a fatal disease. J Pediatr Surg 40:1100–1105

    PubMed  Google Scholar 

  214. MacAllister RJ, Parry H, Kimoto M, Ogawa T, Russell RJ, Hodson H, Whitley GS, Vallance P (1996) Regulation of nitric oxide ­synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol 119:1533–1540

    PubMed  CAS  Google Scholar 

  215. Pierce CM, Krywawych S, Petros AJ (2004) Asymmetric dimethyl arginine and symmetric dimethyl arginine levels in infants with persistent pulmonary hypertension of the newborn. Pediatr Crit Care Med 5:517–520

    PubMed  Google Scholar 

  216. Vosatka RJ, Kashyap S, Trifiletti RR (1994) Arginine deficiency accompanies persistent pulmonary hypertension of the newborn. Biol Neonate 66:65–70

    PubMed  CAS  Google Scholar 

  217. Reddy VM, Wong J, Liddicoat JR, Johengen M, Chang R, Fineman JR (1996) Altered endothelium-dependent responses in lambs with pulmonary hypertension and increased pulmonary blood flow. Am J Physiol 271:H562–H570

    PubMed  CAS  Google Scholar 

  218. Fineman JR, Chang R, Soifer SJ (1992) EDRF inhibition augments pulmonary hypertension in intact newborn lambs. Am J Physiol 262:H1365–H1371

    PubMed  CAS  Google Scholar 

  219. Jun SS, Chen Z, Pace MC, Shaul PW (1999) Glucocorticoids downregulate cyclooxygenase-1 gene expression and prostacyclin synthesis in fetal pulmonary artery endothelium. Circ Res 84:193–200

    PubMed  CAS  Google Scholar 

  220. Arai K, Yanaihara T (1977) Steroid hormone changes in fetal blood during labor. Am J Obstet Gynecol 127:879–883

    PubMed  CAS  Google Scholar 

  221. Shaul PW, Pace MC, Chen Z, Brannon TS (1999) Developmental changes in prostacyclin synthesis are conserved in cultured pulmonary endothelium and vascular smooth muscle. Am J Respir Cell Mol Biol 20:113–121

    PubMed  CAS  Google Scholar 

  222. Jun SS, Chen Z, Pace MC, Shaul PW (1998) Estrogen upregulates cyclooxygenase-1 gene expression in ovine fetal pulmonary artery endothelium. J Clin Invest 102:176–183

    PubMed  CAS  Google Scholar 

  223. Sherman TS, Chambliss KL, Gibson LL, Pace MC, Mendelsohn ME, Pfister SL, Shaul PW (2002) Estrogen acutely activates ­prostacyclin synthesis in ovine fetal pulmonary artery endothelium. Am J Respir Cell Mol Biol 26:610–616

    PubMed  CAS  Google Scholar 

  224. Wojciak-Stothard B, Haworth SG (2006) Perinatal changes in pulmonary vascular endothelial function. Pharmacol Ther 109:78–91

    PubMed  CAS  Google Scholar 

  225. Levin DL (1980) Effects of inhibition of prostaglandin synthesis on fetal development, oxygenation, and the fetal circulation. Semin Perinatol 4:35–44

    PubMed  CAS  Google Scholar 

  226. Stenmark K, James S, Voelkel N, Toews W, Reeves J, Murphy R (1983) Leukotriene C4 and D4 in neonates with hypoxemia and pulmonary hypertension. N Engl J Med 309:77–80

    PubMed  CAS  Google Scholar 

  227. Abman SH, Stenmark KR (1992) Changes in lung eicosanoid ­content during normal and abnormal transition in perinatal lambs. Am J Physiol 262:L214–L222

    PubMed  CAS  Google Scholar 

  228. Hislop AA, Zhao YD, Springall DR, Polak JM, Haworth SG (1995) Postnatal changes in endothelin-1 binding in porcine ­pulmonary vessels and airways. Am J Respir Cell Mol Biol 12:557–566

    PubMed  CAS  Google Scholar 

  229. Ivy DD, Lee DS, Rairigh RL, Parker TA, Abman SH (2004) Endothelin B receptor blockade attenuates pulmonary vasodilation in oxygen-ventilated fetal lambs. Biol Neonate 86:155–159

    PubMed  CAS  Google Scholar 

  230. Black SM, Johengen MJ, Soifer SJ (1998) Coordinated regulation of genes of the nitric oxide and endothelin pathways during the development of pulmonary hypertension in fetal lambs. Pediatr Res 44:821–830

    PubMed  CAS  Google Scholar 

  231. Allen S, Chatfield B, Koppenhafer S, Schaffer M, Wolfe R, Abman S (1993) Circulating immunoreactive endothelin-1 in children with pulmonary hypertension. Association with acute hypoxic pulmonary vasoreactivity. Am Rev Respir Dis 148:519–522

    PubMed  CAS  Google Scholar 

  232. Schindler M, Hatch D, Hislop A, Haworth S (1997) Enhanced constriction of bronchi and pulmonary arteries to endothelin in pulmonary hypertension. Circulation 96:427

    Google Scholar 

  233. McQuillan L, Leung G, Marsden P, Kostyk S, Kourembanas S (1994) Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms. Am J Physiol 267:H1921–H1927

    PubMed  CAS  Google Scholar 

  234. Giaid A, Saleh D (1995) Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 333:214–221

    PubMed  CAS  Google Scholar 

  235. Griffiths M, Evans T (2005) Inhaled nitric oxide therapy in adults. N Engl J Med 353:2683–2695

    PubMed  CAS  Google Scholar 

  236. Barnett C, Machado R (2006) Sildenafil in the treatment of ­pulmonary hypertension. Vasc Health Risk Manag 2:411–422

    PubMed  CAS  Google Scholar 

  237. Mason N, Springall D, Burke M, Pollock J, Mikhail G, Yacoub M, Polak J (1998) High expression of endothelial nitric oxide synthase in plexiform lesions of pulmonary hypertension. J Pathol 185:313–318

    PubMed  CAS  Google Scholar 

  238. Gladwin M, Schechter A (2004) NO contest: nitrite versus S-nitroso-hemoglobin. Circ Res 94:851–855

    PubMed  CAS  Google Scholar 

  239. Bowers R, Cool C, Murphy R, Tuder R, Hopken M, Flores S, Voelkel N (2004) Oxidative stress in severe pulmonary hypertension. Am J Respir Crit Care Med 169:764–769

    PubMed  Google Scholar 

  240. Yildiz P, Oflaz H, Cine N, Erginel-Unaltuna N, Erzengin F, Yilmaz V (2003) Gene polymorphisms of endothelial nitric oxide synthase enzyme associated with pulmonary hypertension in patients with COPD. Respir Med 97:1282–1288

    PubMed  Google Scholar 

  241. Kawaguchi Y, Tochimoto A, Hara M, Kawamoto M, Sugiura T, Katsumata Y, Okada J, Kondo H, Okubo M, Kamatani N (2006) NOS2 polymorphisms associated with the susceptibility to pulmonary arterial hypertension with systemic sclerosis: contribution to the transcriptional activity. Arthritis Res Ther 8:R104

    PubMed  Google Scholar 

  242. Tuder R, Cool C, Geraci M, Wang J, Abman S, Wright L, Badesch D, Voelkel N (1999) Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 159:1925–1932

    PubMed  CAS  Google Scholar 

  243. Christman B, McPherson C, Newman J, King G, Bernard G, Groves B, Loyd J (1992) An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 327:70–75

    PubMed  CAS  Google Scholar 

  244. Voelkel N, Tuder R, Wade K, Höper M, Lepley R, Goulet J, Koller B, Fitzpatrick F (1996) Inhibition of 5-lipoxygenase-activating protein (FLAP) reduces pulmonary vascular reactivity and pulmonary hypertension in hypoxic rats. J Clin Invest 97:2491–2498

    PubMed  CAS  Google Scholar 

  245. Wright L, Tuder R, Wang J, Cool C, Lepley R, Voelkel N (1998) 5-Lipoxygenase and 5-lipoxygenase activating protein (FLAP) immunoreactivity in lungs from patients with primary pulmonary hypertension. Am J Respir Crit Care Med 157:219–229

    PubMed  CAS  Google Scholar 

  246. Jones J, Walker J, Song Y, Weiss N, Cardoso W, Tuder R, Loscalzo J, Zhang Y (2004) Effect of 5-lipoxygenase on the development of pulmonary hypertension in rats. Am J Physiol Heart Circ Physiol 286:H1775–H1784

    PubMed  CAS  Google Scholar 

  247. Song Y, Jones J, Beppu H, Keaney JJ, Loscalzo J, Zhang Y (2005) Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice. Circulation 112:553–562

    PubMed  CAS  Google Scholar 

  248. Giaid A, Yanagisawa M, Langleben D, Michel R, Levy R, Shennib H, Kimura S, Masaki T, Duguid W, Stewart D (1993) Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 328:1732–1739

    PubMed  CAS  Google Scholar 

  249. Langleben D (2007) Endothelin receptor antagonists in the ­treatment of pulmonary arterial hypertension. Clin Chest Med 28:117–125, viii

    Google Scholar 

  250. Loscalzo J, Kohane I, Barabasi A (2007) Human disease classification in the postgenomic era: a complex systems approach to human pathobiology. Mol Syst Biol 3:124

    PubMed  Google Scholar 

  251. Zhu P, Huang L, Ge X, Yan F, Wu R, Ao Q (2006) Transdifferentiation of pulmonary arteriolar endothelial cells into smooth muscle-like cells regulated by myocardin involved in hypoxia-induced pulmonary vascular remodelling. Int J Exp Pathol 87:463–474

    PubMed  CAS  Google Scholar 

  252. Sakao S, Taraseviciene-Stewart L, Cool C, Tada Y, Kasahara Y, Kurosu K, Tanabe N, Takiguchi Y, Tatsumi K, Kuriyama T, Voelkel N (2007) VEGF-R blockade causes endothelial cell apoptosis, expansion of surviving CD34+ precursor cells and transdifferentiation to smooth muscle-like and neuronal-like cells. FASEB J 21:3640–3652

    PubMed  CAS  Google Scholar 

  253. Humbert M, Sitbon O, Simonneau G (2004) Treatment of ­pulmonary arterial hypertension. N Engl J Med 351(14):1425–1436

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by NIH grants HL61795, HV28718, and HL81587. We thank Stephanie Tribuna for expert secretarial assistance.

Author information

Authors and Affiliations

  1. Brigham and Women’s Hospital, Harvard Medical School, Boston, 0415, MA, USA

    Stephen Y. Chan

Authors
  1. Stephen Y. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joseph Loscalzo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen Y. Chan .

Editor information

Editors and Affiliations

  1. Departments of Medicine, COMRB Rm. 3131 (MC 719), University of Illinois at Chicago, 909 South Wolcott Avenue, Chicago, 60612, Illinois, USA

    Jason X. -J. Yuan

  2. 310 Admin.Office Building (MC 672), University of Illinois at Chicago, 1737 W. Polk Street, Suite 310, Chicago, 60612, Illinois, USA

    Joe G.N. Garcia

  3. Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0623, California, USA

    John B. West

  4. Dept. Pulmonary & Critical Care Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, 02114, Massachusetts, USA

    Charles A. Hales

  5. Department of Medicine, University of Chicago Medical Center, 5841 S. Maryland Ave., Chicago, 60637, Illinois, USA

    Stuart Rich

  6. Department of Medicine, University of Chicago School of Medicine, 5841 S. Maryland Ave., Chicago, 60637, Illinois, USA

    Stephen L. Archer

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Chan, S.Y., Loscalzo, J. (2011). Endothelial Regulation of Pulmonary Vascular Tone. In: Yuan, JJ., Garcia, J., West, J., Hales, C., Rich, S., Archer, S. (eds) Textbook of Pulmonary Vascular Disease. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-87429-6_11

Download citation

  • DOI: https://doi.org/10.1007/978-0-387-87429-6_11

  • Published:

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-387-87428-9

  • Online ISBN: 978-0-387-87429-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation