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The Influence of the Major Vasoactive Mediators Relevant to the Pathogenesis of Pulmonary Hypertension

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Abstract

The pulmonary circulation exhibits unique responses to vasoactive factors compared with the systemic circulation owing to the many differences in the structure and function of the systemic and pulmonary circulations. The pulmonary circulation is normally virtually fully vasodilated, whereas the systemic circulation is tonically vasoconstricted. This in itself imparts a unique responses to vasoactive factors to the pulmonary arterial bed as vascular tone per se alters the responses to many vasoactive factors. In addition, in vivo and in vitro studies suggest that the pulmonary arterial circulation is composed of phenotypically distinct heterogeneous populations of smooth muscle cells with unique developmental lineages. They differ in their vasoactivity and ability to proliferate and therefore there are regional differences in the responses to many vasoactive factors between the smaller, distal pulmonary resistance arteries and the larger, proximal elastic pulmonary arteries. This differential responsiveness might be expected as the proximal and distal pulmonary arteries have differential developmental origins and proximal pulmonary arteries develop via angiogenesis, whereas distal vessels form by vasculogenesis. There are differences between the proximal and distal pulmonary arteries, for example, in the distribution of K+ channels, endothelin receptors, prostacyclin synthase, nitric oxide (NO) production, NO synthase expression, phosphodiesterase activity, and store-operated Ca2 + entry. This chapter describes the normal pharmacology of the major endogenous vasoactive factors involved in the pathogenic mechanisms of pulmonary arterial hypertension, pulmonary artery regional diversity, and how this alters following experimental and clinical pulmonary hypertension.

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References

  1. MacLean MR (1999) Pulmonary hypertension, anorexigens and 5-HT: pharmacological synergism in action? Trends Pharmacol Sci 20:490–495

    PubMed  CAS  Google Scholar 

  2. Stenmark KR, Frid M, Nemenoff R, Dempsey EC, Das M (1999) Hypoxia induces cell-specific changes in gene expression in vascular wall cells: implications for pulmonary hypertension. Hypoxia 474:231–258

    CAS  Google Scholar 

  3. 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 

  4. Schachtner SK, Wang Y, Scott Baldwin H (2000) Qualitative and quantitative analysis of embryonic pulmonary vessel formation. Am J Respir Cell Mol Biol 22:157–165

    PubMed  CAS  Google Scholar 

  5. Davie N, Haleen SJ, Upton PD, Polak JM, Yacoub MH, Morrell NW et al (2002) ETA and ETB receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit Care Med 165:398–405

    PubMed  Google Scholar 

  6. MacLean MR, McCulloch KM, Baird M (1994) Endothelin ETA-receptor-mediated and ETB-receptor-mediated vasoconstriction in rat pulmonary-arteries and arterioles. J Cardiovasc Pharmacol 23:838–845

    PubMed  CAS  Google Scholar 

  7. Weir EK, Olschewski A (2006) Role of ion channels in acute and chronic responses of the pulmonary vasculature to hypoxia. Cardiovasc Res 71:630–641

    PubMed  CAS  Google Scholar 

  8. Miike T, Shirahase H, Kanda M, Kunishiro K, Kurahashi K (2008) Regional heterogeneity of substance P-induced endothelium-dependent contraction, relaxation, and -independent contraction in rabbit pulmonary arteries. Life Sci 83:810–814

    PubMed  CAS  Google Scholar 

  9. Steudel W, Watanabe M, Dikranian K, Jacobson M, Jones RC (1999) Expression of nitric oxide synthase isoforms (NOS II and NOS III) in adult rat lung in hyperoxic pulmonary hypertension. Cell Tissue Res 295:317–329

    PubMed  CAS  Google Scholar 

  10. Michelakis ED, Reeve HL, Huang JM, Tolarova S, Nelson DP, Weir EK et al (1997) Potassium channel diversity in vascular smooth muscle cells. Can J Physiol Pharmacol 75:889–897

    PubMed  CAS  Google Scholar 

  11. Konduri GG, Bakhutashvili I, Frenn R, Chandrasekhar I, Jacobs ER, Khanna AK (2004) P2Y purine receptor responses and expression in the pulmonary circulation of juvenile rabbits. Am J Physiol Heart Circ Physiol 287:H157–H164

    PubMed  CAS  Google Scholar 

  12. MacLean MR, Johnston ED, McCulloch KM, Pooley L, Houslay MD, Sweeney G (1997) Phosphodiesterase isoforms in the pulmonary arterial circulation of the rat: changes in pulmonary hypertension. J Pharmacol Exp Ther 283:619–624

    PubMed  CAS  Google Scholar 

  13. Lu W, Wang J, Shimoda LA, Sylvester JT (2008) Differences in STIM1 and TRPC expression in proximal and distal pulmonary arterial smooth muscle are associated with differences in Ca2+ responses to hypoxia. Am J Physiol Lung Cell Mol Physiol 295:L104–L113

    PubMed  CAS  Google Scholar 

  14. McCulloch KM, Kempsill FEJ, Buchanan KJ, Gurney AM (2000) Regional distribution of potassium currents in the rabbit pulmonary arterial circulation. Exp Physiol 85:487–496

    PubMed  CAS  Google Scholar 

  15. Tuder R, Cool C, Geraci M, Wang J, Abman S, Wright L et al (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 

  16. Schwenke DO, Pearson JT, Umetani K, Kangawa K, Shirai M (2007) Imaging of the pulmonary circulation in the closed-chest rat using synchrotron radiation microangiography. J Appl Physiol 102:787–793

    PubMed  Google Scholar 

  17. Dinh-Xuan AT (1992) Endothelial modulation of pulmonary vascular tone. Eur Respir J 5:757–762

    PubMed  CAS  Google Scholar 

  18. Wharton J, Davie N, Upton PD, Yacoub MH, Polak JM, Morrell NW (2000) Prostacyclin analogues differentially inhibit growth of distal and proximal human pulmonary artery smooth muscle cells. Circulation 102:3130–3136

    PubMed  CAS  Google Scholar 

  19. Davie NJ, Gerasimovskaya EV, Hofmeister SE, Richman AP, Jones PL, Reeves JT et al (2006) Pulmonary artery adventitial fibroblasts cooperate with vasa vasorum endothelial cells to regulate vasa vasorum neovascularization: a process mediated by hypoxia and endothelin-1. Am J Pathol 168:1793–1807

    PubMed  CAS  Google Scholar 

  20. Lee SL, Wang WW, Fanburg BL (1998) Superoxide as an intermediate signal for serotonin-induced mitogenesis. Free Radic Biol Med 24:855–858

    PubMed  Google Scholar 

  21. MacLean MR (1998) Endothelin-1: a mediator of pulmonary hypertension? Pulm Pharmacol Ther 11:125–132

    PubMed  CAS  Google Scholar 

  22. MacLean MR (1999) Endothelin-1 and serotonin: mediators of primary and secondary pulmonary hypertension? J Lab Clin Med 134:105–114

    PubMed  CAS  Google Scholar 

  23. Davenport AP (2002) International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacol Rev 54:219–226

    PubMed  CAS  Google Scholar 

  24. Dupuis J, Goresky CA, Fournier A (1996) Pulmonary clearance of circulating endothelin-1 in dogs in vivo: exclusive role of ETB receptors. J Appl Physiol 81:1510–1515

    PubMed  CAS  Google Scholar 

  25. Fukuroda T, Kobayashi M, Ozaki S, Yano M, Miyauchi T, Onizuka M et al (1994) Endothelin receptor subtypes in human versus rabbit pulmonary-arteries. J Appl Physiol 76:1976–1982

    PubMed  CAS  Google Scholar 

  26. McCulloch KM, MacLean MR (1995) EndothelinB receptor-mediated contraction of human and rat pulmonary resistance arteries and the effect of pulmonary-hypertension on endothelin responses in the rat. J Cardiovasc Pharmacol 26:S169–S176

    PubMed  CAS  Google Scholar 

  27. McCulloch KM, Docherty C, MacLean MR (1998) Endothelin receptors mediating contraction of rat and human pulmonary resistance arteries: effect of chronic hypoxia in the rat. Br J Pharmacol 123:1621–1630

    PubMed  CAS  Google Scholar 

  28. MacLean MR, Docherty CC, McCulloch KM, Morecroft I (1998) Effect of novel mixed ETA/ETB antagonists on responses to ET-1 in human small muscular pulmonary arteries. Pulm Pharmacol Ther 11:147–149

    PubMed  CAS  Google Scholar 

  29. Provencher S, Sitbon O, Simonneau G (2005) Treatment of pulmonary arterial hypertension with bosentan: from pathophysiology to clinical evidence. Expert Opin Pharmacother 6:1337–1348

    PubMed  CAS  Google Scholar 

  30. Sato K, Oka M, Hasunuma K, Ohnishi M, Sato K, Kira S (1995) Effects of separate and combined ETA and ETB blockade on ET-1-induced constriction in perfused rat lungs. Am J Physiol 13:L668–L672

    Google Scholar 

  31. Hay DW, Luttmann MA, Pullen MA, Nambi P (1998) Functional and binding characterization of endothelin receptors in human bronchus: evidence for a novel endothelin B receptor subtype? J Pharmacol Exp Ther 284:669–677

    PubMed  CAS  Google Scholar 

  32. Docherty CC, MacLean MR (1998) EndothelinB receptors in rabbit pulmonary resistance arteries: effect of left ventricular dysfunction. J Pharmacol Exp Ther 284(3):895–903

    PubMed  CAS  Google Scholar 

  33. Ladouceur DM, Flynn MA, Keiser JA, Reynolds E, Haleen SJ (1993) ETA and ETB receptors coexist on rabbit pulmonary artery vascular smooth muscle mediating contraction. Biochem Biophys Res Commun 196:209–215

    PubMed  CAS  Google Scholar 

  34. MacLean MR, McCulloch KM, Baird M (1995) Effects of ­pulmonary-hypertension on vasoconstrictor responses to endothelin-1 and sarafotoxin S6C and on inherent tone in rat pulmonary arteries. J Cardiovasc Pharmacol 26:822–830

    PubMed  CAS  Google Scholar 

  35. Li H, Elton TS, Chen YF, Oparil S (1994) Increased endothelin receptor gene expression in hypoxic rat lung. Am J Physiol 266:L553–L560

    PubMed  CAS  Google Scholar 

  36. Hervé P, Launay JM, Scrobohaci ML, Brenot F, Simonneau G, Petitpretz P et al (1995) Increased plasma serotonin in primary pulmonary hypertension. Am J Med 99:249–254

    PubMed  Google Scholar 

  37. Hervé P, Drouet L, Dosquet C, Launay JM, Rain B, Simonneau G et al (1990) Primary pulmonary hypertension in a patient with a familial platelet storage pool disease: role of serotonin. Am J Med 89:117–120

    PubMed  Google Scholar 

  38. Dempsie Y, MacLean MR (2008) Pulmonary hypertension: therapeutic targets within the serotonin system. Br J Pharmacol 155:455–462

    PubMed  CAS  Google Scholar 

  39. Suzuki YJ, Day RM, Tan CC, Sandven TH, Liang QR, Molkentin JD et al (2003) Activation of GATA-4 by serotonin in pulmonary artery smooth muscle cells. J Biol Chem 278:17525–17531

    PubMed  CAS  Google Scholar 

  40. Alexander SPH, Mathie A, Peters JA (2005) Guide to receptors and channels, 1st edition (2005 revision). Br J Pharmacol 144:S1–S128

    PubMed  Google Scholar 

  41. Frishman WH, Huberfeld S, Okin S, Wang YH, Kumar A, Shareef B (1995) Serotonin and serotonin antagonism in cardiovascular and non-cardiovascular disease. J Clin Pharmacol 35:541–572

    PubMed  CAS  Google Scholar 

  42. McGoon MD, Vlietstra RE (1987) Acute hemodynamic response to the S2-serotonergic receptor antagonist, ketanserin, in patients with primary pulmonary hypertension. Int J Cardiol 14:303–309

    PubMed  CAS  Google Scholar 

  43. MacIntyre PD, Bhargava B, Hogg KJ, Gemmill JD, Hillis WS (1993) Effect of subcutaneous sumatriptan, a selective 5HT1 agonist, on the systemic, pulmonary, and coronary circulation. Circulation 87:401–405

    PubMed  CAS  Google Scholar 

  44. MacLean MR, Clayton RA, Templeton AGB, Morecroft I (1996) Evidence for 5-HT1-like receptor-mediated vasoconstriction in human pulmonary artery. Br J Pharmacol 119:277–282

    PubMed  CAS  Google Scholar 

  45. Morecroft I, Heeley RP, Prentice HM, Kirk A, MacLean MR (1999) 5-Hydroxytryptamine receptors mediating contraction in human small muscular pulmonary arteries: importance of the 5-HT1B receptor. Br J Pharmacol 128:730–734

    PubMed  CAS  Google Scholar 

  46. Launay JM, Hervé P, Peoc’h K, Tournois C, Callebert J, Nebigil CG et al (2002) Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat Med 8:1129–1135

    PubMed  CAS  Google Scholar 

  47. Keegan A, Morecroft I, Smillie D, Hicks MN, MacLean MR (2001) Contribution of the 5-HT1B receptor to hypoxia-induced pulmonary hypertension – converging evidence using 5-HT1B-receptor knockout mice and the 5-HT1B/1D-receptor antagonist GR127935. Circ Res 89:1231–1239

    PubMed  CAS  Google Scholar 

  48. Rondelet B, Van Beneden R, Kerbaul F, Motte S, Fesler P, McEntee K et al (2003) Expression of the serotonin 1b receptor in experimental pulmonary hypertension. Eur Respir J 22:408–412

    PubMed  CAS  Google Scholar 

  49. Lawrie A, Spiekerkoetter E, Martinez EC, Ambartsumian N, Sheward WJ, MacLean MR et al (2005) Interdependent serotonin transporter and receptor pathways regulate S100A4/Mts1, a gene associated with pulmonary vascular disease. Circ Res 97:227–235

    PubMed  CAS  Google Scholar 

  50. Cogolludo A, Moreno L, Lodi F, Frazziano G, Cobeno L, Tamargo J et al (2006) Serotonin inhibits voltage-gated K+ currents in pulmonary artery smooth muscle cells – role of 5-HT2A receptors, caveolin-1, and KV1.5 channel internalization. Circ Res 98:931–938

    PubMed  CAS  Google Scholar 

  51. Welsh DJ, Harnett M, Maclean M, Peacock AJ (2004) Proliferation and signaling in fibroblasts – role of 5-hydroxytryptamine2A receptor and transporter. Am J Respir Crit Care Med 170:252–259

    PubMed  Google Scholar 

  52. Callebert J, Esteve JM, Hervé P, Peoc’h K, Tournois C, Drouet L et al (2006) Evidence for a control of plasma serotonin levels by 5-hydroxytryptamine2B receptors in mice. J Pharmacol Exp Ther 317:724–731

    PubMed  CAS  Google Scholar 

  53. Blanpain C, Le Poul E, Parma J, Knoop C, Detheux M, Parmentier M et al (2003) Serotonin 5-HT2B receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension. Cardiovasc Res 60:518–528

    PubMed  CAS  Google Scholar 

  54. Eddahibi S, Humbert M, Fadel E, Raffestin B, Darmon M, Capron F et al (2001) Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 108:1141–1150

    PubMed  CAS  Google Scholar 

  55. Machado RD, Koehler R, Glissmeyer E, Veal C, Suntharalingam J, Kim M et al (2006) Genetic association of the serotonin transporter in pulmonary arterial hypertension. Am J Respir Crit Care Med 173:793–797

    PubMed  CAS  Google Scholar 

  56. Willers ED, Newman JH, Loyd JE, Robbins IM, Wheeler LA, Prince MA et al (2006) Serotonin transporter polymorphisms in familial and idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 173:798–802

    PubMed  CAS  Google Scholar 

  57. Eddahibi S, Hanoun N, Lanfumey L, Lesch KP, Raffestin B, Hamon M et al (2000) Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest 105:1555–1562

    PubMed  CAS  Google Scholar 

  58. MacLean MR, Deuchar GA, Hicks MN, Morecroft I, Shen SB, Sheward J et al (2004) Overexpression of the 5-hydroxytryptamine transporter gene – effect on pulmonary hemodynamics and hypoxia-induced pulmonary hypertension. Circulation 109:2150–2155

    PubMed  CAS  Google Scholar 

  59. Guignabert C, Izikki M, Tu LI, Li ZL, Zadigue P, Barlier-Mur AM et al (2006) Transgenic mice overexpressing the 5-hydroxytryptamine transporter gene in smooth muscle develop pulmonary hypertension. Circ Res 98:1323–1330

    PubMed  CAS  Google Scholar 

  60. Marcos E, Fadel E, Sanchez O, Humbert M, Dartevelle P, Simonneau G et al (2004) Serotonin-induced smooth muscle hyperplasia in various forms of human pulmonary hypertension. Circ Res 94:1263–1270

    PubMed  CAS  Google Scholar 

  61. Lee SL, Wang WW, Lanzillo JJ, Fanburg BL (1994) Serotonin produces both hyperplasia and hypertrophy of bovine pulmonary artery smooth muscle cells in culture. Am J Physiol 266:L46–L52

    PubMed  CAS  Google Scholar 

  62. Liu YL, Suzuki YJ, Day RM, Fanburg BL (2004) Rho kinase-induced nuclear translocation of ERK1/ERK2 in smooth muscle cell mitogenesis caused by serotonin. Circ Res 95:579–586

    PubMed  CAS  Google Scholar 

  63. Morecroft I, Loughlin L, Nilsen M, Colston J, Dempsie Y, Sheward J et al (2005) Functional interactions between 5-hydroxytryptamine receptors and the serotonin transporter in pulmonary arteries. J Pharmacol Exp Ther 313:539–548

    PubMed  CAS  Google Scholar 

  64. Lee SL, Wang WW, Finlay GA, Fanburg BL (1999) Serotonin stimulates mitogen-activated protein kinase activity through the formation of superoxide anion. Am J Physiol 277:L282–L291

    PubMed  CAS  Google Scholar 

  65. Guilluy C, Rolli-Derkinderen M, Tharaux PL, Melino G, Pacaud P, Loirand G (2007) Transglutaminase-dependent RhoA activation and depletion by serotonin in vascular smooth muscle cells. J Biol Chem 282:2918–2928

    PubMed  CAS  Google Scholar 

  66. Walther DJ, Peter J-U, Winter S, Holtje M, Paulmann N, Grohmann M et al (2003) Serotonylation of small GTPases is a signal transduction pathway that triggers platelet α-granule release. Cell 115:851–862

    PubMed  CAS  Google Scholar 

  67. Mair KM, MacLean MR, Morecroft I, Dempsie Y, Palmer TM (2008) Novel interactions between the 5-HT transporter, 5-HT1B receptors and Rho kinase in vivo and in pulmonary fibroblasts. Br J Pharmacol 155:606–616

    PubMed  CAS  Google Scholar 

  68. Walther DJ, Bader M (2003) A unique central tryptophan hydroxylase isoform. Biochem Pharmacol 66:1673–1680

    PubMed  CAS  Google Scholar 

  69. Sullivan CC, Du L, Chu D, Cho AJ, Kido M, Wolf PL et al (2003) Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway. Proc Natl Acad Sci U S A 100:12331–12336

    PubMed  CAS  Google Scholar 

  70. Eddahibi S, Guignabert C, Barlier-Mur AM, Dewachter L, Fadel E, Dartevelle P et al (2006) Cross talk between endothelial and smooth muscle cells in pulmonary hypertension – critical role for serotonin-induced smooth muscle hyperplasia. Circulation 113:1857–1864

    PubMed  CAS  Google Scholar 

  71. Morecroft I, Dempsie Y, Bader M, Walther DJ, Kotnik K, Loughlin L et al (2007) Effect of tryptophan hydroxylase 1 deficiency on the development of hypoxia-induced pulmonary hypertension. Hypertension 49:232–236

    PubMed  CAS  Google Scholar 

  72. Dempsie Y, Morecroft I, Welsh DJ, MacRitchie NA, Herold N, Loughlin L et al (2008) Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice. Circulation 117:2928–2937

    PubMed  CAS  Google Scholar 

  73. Klinger JR (2007) The nitric oxide/cGMP signaling pathway in pulmonary hypertension. Clin Chest Med 28:143–167

    PubMed  Google Scholar 

  74. Coggins MP, Bloch KD (2007) Nitric oxide in the pulmonary vasculature. Arterioscler Thromb Vasc Biol 27:1877–1885

    PubMed  CAS  Google Scholar 

  75. Andriantsitohaina R, Lagaud GJL, Andre A, Muller B, Stoclet JC (1995) Effects of cGMP on calcium handling in ATP-stimulated rat resistance arteries. Am J Physiol 37:H1223–H1231

    Google Scholar 

  76. Furukawa K, Tawada Y, Shigekawa M (1988) Regulation of the plasma membrane Ca2+ pump by cyclic nucleotides in cultured vascular smooth muscle cells. J Biol Chem 263:8058–8065

    PubMed  CAS  Google Scholar 

  77. Furukawa K, Ohshima N, Tawada-Iwata Y, Shigekawa M (1991) Cyclic GMP stimulates Na+/Ca2+ exchange in vascular smooth muscle cells in primary culture. J Biol Chem 266:12337–12341

    PubMed  CAS  Google Scholar 

  78. Komalavilas P, Lincoln TM (1994) Phosphorylation of the inositol 1,4,5-trisphosphate receptor by cyclic GMP-dependent protein kinase. J Biol Chem 269:8701–8707

    PubMed  CAS  Google Scholar 

  79. Sauzeau V, Le Jeune H, Cario-Toumaniantz C, Smolenski A, Lohmann SM, Bertoglio J et al (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 

  80. Jourdan KB, Evans TW, Lamb NJ, Goldstraw P, Mitchell JA (1999) Autocrine function of inducible nitric oxide synthase and cyclooxygenase-2 in proliferation of human and rat pulmonary artery smooth-muscle cells – species variation. Am J Respir Cell Mol Biol 21:105–110

    PubMed  CAS  Google Scholar 

  81. Ambalavanan N, Mariani G, Bulger A, Philips JB (1999) Role of nitric oxide in regulating neonatal porcine pulmonary artery smooth muscle cell proliferation. Biol Neonate 76:291–300

    PubMed  CAS  Google Scholar 

  82. Krick S, Platoshyn O, Sweeney M, McDaniel SS, Zhang S, Rubin LJ et al (2002) Nitric oxide induces apoptosis by activating K+ channels in pulmonary vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 282:H184–H193

    PubMed  CAS  Google Scholar 

  83. Smith JD, McLean SD, Nakayama DK (1998) Nitric oxide causes apoptosis in pulmonary vascular smooth muscle cells. J Surg Res 79:121–127

    PubMed  CAS  Google Scholar 

  84. Pollman MJ, Yamada T, Horiuchi M, Gibbons GH (1996) Vasoactive substances regulate vascular smooth muscle cell apoptosis. Countervailing influences of nitric oxide and angiotensin II. Circ Res 79:748–756

    PubMed  CAS  Google Scholar 

  85. Costa RS, Assreuy J (2005) Multiple potassium channels mediate nitric oxide-induced inhibition of rat vascular smooth muscle cell proliferation. Nitric Oxide 13:145–151

    PubMed  CAS  Google Scholar 

  86. Zuckerbraun BS, Stoyanovsky DA, Sengupta R, Shapiro RA, Ozanich BA, Rao J et al (2007) Nitric oxide-induced inhibition of smooth muscle cell proliferation involves S-nitrosation and inactivation of RhoA. Am J Physiol Cell Physiol 292:C824–C831

    PubMed  CAS  Google Scholar 

  87. Steudel W, Ichinose F, Huang PL, Hurford WE, Jones RC, Bevan JA et al (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 

  88. Fagan KA, Tyler RC, Sato K, Fouty BW, Morris KG Jr, Huang PL et al (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 

  89. Fagan KA, Fouty BW, Tyler RC, Morris KG Jr, Hepler LK, Sato K et al (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 

  90. Rich GF, Roos CM, Anderson SM, Urich DC, Daugherty MO, Johns RA (1993) Inhaled nitric oxide: dose response and the effects of blood in the isolated rat lung. J Appl Physiol 75:1278–1284

    PubMed  CAS  Google Scholar 

  91. Frostell CG, Blomqvist H, Hedenstierna G, Lundberg J, Zapol WM (1993) Inhaled nitric oxide selectively reverses human hypoxic pulmonary vasoconstriction without causing systemic vasodilation. Anesthesiology 78:427–435

    PubMed  CAS  Google Scholar 

  92. Jiang BH, Maruyama J, Yokochi A, Amano H, Mitani Y, Maruyama K (2002) Correlation of inhaled nitric-oxide induced reduction of pulmonary artery pressure and vascular changes. Eur Respir J 20:52–58

    PubMed  CAS  Google Scholar 

  93. Weitzberg E, Rudehill A, Lundberg JM (1993) Nitric oxide inhalation attenuates pulmonary hypertension and improves gas exchange in endotoxin shock. Eur J Pharmacol 233:85–94

    PubMed  CAS  Google Scholar 

  94. Fratacci MD, Frostell CG, Chen TY, Wain JC Jr, Robinson DR, Zapol WM (1991) Inhaled nitric oxide. A selective pulmonary vasodilator of heparin-protamine vasoconstriction in sheep. Anesthesiology 75:990–999

    PubMed  CAS  Google Scholar 

  95. Liu L, Liu H, Visner G, Fletcher BS (2006) Sleeping beauty-mediated eNOS gene therapy attenuates monocrotaline-induced pulmonary hypertension in rats. FASEB J 20:2594–2596

    PubMed  CAS  Google Scholar 

  96. Babaei S, Stewart DJ (2002) Overexpression of endothelial NO synthase induces angiogenesis in a co-culture model. Cardiovasc Res 55:190–200

    PubMed  CAS  Google Scholar 

  97. Zhao YD, Courtman DW, Ng DS, Robb MJ, Deng YP, Trogadis J et al (2006) Microvascular regeneration in established pulmonary hypertension by angiogenic gene transfer. Am J Respir Cell Mol Biol 35:182–189

    PubMed  CAS  Google Scholar 

  98. Channick RN, Newhart JW, Johnson FW, Williams PJ, Auger WR, Fedullo PF et al (1996) Pulsed delivery of inhaled nitric oxide to patients with primary pulmonary hypertension: an ambulatory delivery system and initial clinical tests. Chest 109:1545–1549

    PubMed  CAS  Google Scholar 

  99. Post MC, Janssens S, Van de WF, Budts W (2004) Responsiveness to inhaled nitric oxide is a predictor for mid-term survival in adult patients with congenital heart defects and pulmonary arterial hypertension. Eur Heart J 25:1651–1656

    PubMed  CAS  Google Scholar 

  100. Mitchell JA, Ali F, Bailey L, Moreno L, Harrington LS (2008) Role of nitric oxide and prostacyclin as vasoactive hormones released by the endothelium. Exp Physiol 93:141–147

    PubMed  CAS  Google Scholar 

  101. Gryglewski RJ (2008) Prostacyclin among prostanoids. Pharmacol Rep 60:3–11

    PubMed  CAS  Google Scholar 

  102. Schwarz UR, Walter U, Eigenthaler M (2001) Taming platelets with cyclic nucleotides. Biochem Pharmacol 62:1153–1161

    PubMed  CAS  Google Scholar 

  103. Shaywitz AJ, Greenberg ME (1999) CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 68:821–861

    PubMed  CAS  Google Scholar 

  104. Christman BW, Mcpherson CD, Newman JH, King GA, Bernard GR, Groves BM et al (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 

  105. Higenbottam T, Wells F, Wheeldon D, Wallwork J (1984) ­Long-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin). Lancet 1:1046–1047

    PubMed  CAS  Google Scholar 

  106. Rubin LJ, Mendoza J, Hood M, Mcgoon M, Barst R, Williams WB et al (1990) Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol) – results of a randomized trial. Ann Intern Med 112:485–491

    PubMed  CAS  Google Scholar 

  107. Humbert M, Sanchez O, Fartoukh M, Jagot JL, Le Gall C, Sitbon O et al (1999) Short-term and long-term epoprostenol (prostacyclin) therapy in pulmonary hypertension secondary to connective tissue diseases: results of a pilot study. Eur Respir J 13:1351–1356

    PubMed  CAS  Google Scholar 

  108. McLaughlin VV, Genthner DE, Panella MM, Hess DM, Rich S (1999) Compassionate use of continuous prostacyclin in the management of secondary pulmonary hypertension: a case series. Ann Intern Med 130:740–743

    PubMed  CAS  Google Scholar 

  109. McLaughlin VV, Shillington A, Rich S (2002) Survival in primary pulmonary hypertension – the impact of epoprostenol therapy. Circulation 106:1477–1482

    PubMed  CAS  Google Scholar 

  110. Chin KM, Rubin LJ (2008) Pulmonary arterial hypertension. J Am Coll Cardiol 51:1527–1538

    PubMed  Google Scholar 

  111. Higenbottam T, Butt AY, McMahon A, Westerbeck R, Sharples L (1998) Long term intravenous prostaglandin (epoprostenol or iloprost) for treatment of severe pulmonary hypertension. Heart 80:151–155

    PubMed  CAS  Google Scholar 

  112. MacLean MR, Sweeney G, Baird M, McCulloch KM, Houslay M, Morecroft I (1996) 5-Hydroxytryptamine receptors mediating vasoconstriction in pulmonary arteries from control and pulmonary hypertensive rats. Br J Pharmacol 119:917–930

    PubMed  CAS  Google Scholar 

  113. Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58:488–520

    PubMed  CAS  Google Scholar 

  114. Murray F, Patel HH, Suda RYS, Zhang S, Thistlethwaite PA, Yuan JX-J et al (2007) Expression and activity of cAMP phosphodiesterase isoforms in pulmonary artery smooth muscle cells from patients with pulmonary hypertension: role for PDE1. Am J Physiol Lung Cell Mol Physiol 292:L294–L303

    PubMed  CAS  Google Scholar 

  115. Yan C, Zhao AZ, Bentley JK, Beavo JA (1996) The calmodulin-dependent phosphodiesterase gene PDE1C encodes several functionally different splice variants in a tissue-specific manner. J Biol Chem 271:25699–25706

    PubMed  CAS  Google Scholar 

  116. Rybalkin SD, Bornfeldt KE, Sonnenburg WK, Rybalkina IG, Kwak KS, Hanson K et al (1997) Calmodulin-stimulated cyclic nucleotide phosphodiesterase (PDE1C) is induced in human arterial smooth muscle cells of the synthetic, proliferative phenotype. J Clin Invest 100:2611–2621

    PubMed  CAS  Google Scholar 

  117. Schermuly RT, Pullamsetti SS, Kwapiszewska G, Dumitrascu R, Tian X, Weissmann N et al (2007) Phosphodiesterase 1 upregulation in pulmonary arterial hypertension target for reverse-remodeling therapy. Circulation 115:2331–2339

    PubMed  CAS  Google Scholar 

  118. Lugnier C (2006) Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther 109:366–398

    PubMed  CAS  Google Scholar 

  119. Wagner RS, Smith CJ, Taylor AM, Rhoades RA (1997) Phosphodi­esterase inhibition improves agonist-induced relaxation of hypertensive pulmonary arteries. J Pharmacol Exp Ther 282:1650–1657

    PubMed  CAS  Google Scholar 

  120. Murray F, MacLean MR, Pyne NJ (2002) Increased expression of the cGMP-inhibited cAMP-specific (PDE3) and cGMP binding cGMP-specific (PDE5) phosphodiesterases in models of pulmonary hypertension. Br J Pharmacol 137:1187–1194

    PubMed  CAS  Google Scholar 

  121. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, Dibianco R, Zeldis SM et al (1991) Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 325:1468–1475

    PubMed  CAS  Google Scholar 

  122. Houslay MD, Baillie GS, Maurice DH (2007) cAMP-Specific phosphodiesterase-4 enzymes in the cardiovascular system: a molecular toolbox for generating compartmentalized cAMP signaling. Circ Res 100:950–966

    PubMed  CAS  Google Scholar 

  123. Millen J, MacLean MR, Houslay MD (2006) Hypoxia-induced remodelling of PDE4 isoform expression and cAMP handling in human pulmonary artery smooth muscle cells. Eur J Cell Biol 85:679–691

    PubMed  CAS  Google Scholar 

  124. Phillips PG, Long L, Wilkins MR, Morrell NW (2005) cAMP phosphodiesterase inhibitors potentiate effects of prostacyclin analogs in hypoxic pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 288:L103–L115

    PubMed  CAS  Google Scholar 

  125. Wharton J, Strange JW, Moller GMO, Growcott EJ, Ren XH, Franklyn AP et al (2005) Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med 172:105–113

    PubMed  Google Scholar 

  126. Corbin JD, Beasley A, Blount MA, Francis SH (2005) High lung PDE5: a strong basis for treating pulmonary hypertension with PDE5 inhibitors. Biochem Biophys Res Commun 334: 930–938

    PubMed  CAS  Google Scholar 

  127. Sebkhi A, Strange JW, Phillips SC, Wharton J, Wilkins MR (2003) Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension. Circulation 107:3230–3235

    PubMed  CAS  Google Scholar 

  128. Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A et al (2001) Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 104:424–428

    PubMed  CAS  Google Scholar 

  129. Schermuly RT, Kreisselmeier KP, Ghofrani HA, Yilmaz H, Butrous G, Ermert L et al (2004) Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats. Am J Respir Crit Care Med 169:39–45

    PubMed  Google Scholar 

  130. Sastry BKS, Narasimhan C, Reddy NK, Raju BS (2004) Clinical efficacy of sildenafil in primary pulmonary hypertension – a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 43:1149–1153

    PubMed  CAS  Google Scholar 

  131. Bobik A (2006) Transforming growth factor-βs and vascular disorders. Arterioscler Thromb Vasc Biol 26:1712–1720

    PubMed  CAS  Google Scholar 

  132. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA, Loyd JE et al (2000) Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension. Nat Genet 26:81–84

    PubMed  CAS  Google Scholar 

  133. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G et al (2000) Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67:737–744

    PubMed  CAS  Google Scholar 

  134. Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC et al (2000) Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-β family. J Med Genet 37:741–745

    PubMed  CAS  Google Scholar 

  135. Baloira A, Vilarino C, Leiro V, Valverde D (2008) Mutations in the gene encoding bone morphogenetic protein receptor 2 in patients with idiopathic pulmonary arterial hypertension. Arch Bronconeumol 44:29–34

    PubMed  Google Scholar 

  136. Sankelo M, Flanagan JA, Machado R, Harrison R, Rudarakanchana N, Morrell N et al (2005) BMPR2 mutations have short lifetime expectancy in primary pulmonary hypertension. Hum Mutat 26:119–124

    PubMed  CAS  Google Scholar 

  137. Fujiwara M, Yagi H, Matsuoka R, Akimoto K, Furutani M, Imamura S et al (2008) Implications of mutations of activin receptor-like kinase 1 gene (ALK1) in addition to bone morphogenetic protein receptor II gene (BMPR2) in children with pulmonary arterial hypertension. Circ J 72:127–133

    PubMed  CAS  Google Scholar 

  138. Trembath RC (2001) Mutations in the TGF-beta type 1 receptor, ALK1, in combined primary pulmonary hypertension and hereditary haemorrhagic telangiectasia, implies pathway specificity. J Heart Lung Transplant 20:175

    PubMed  Google Scholar 

  139. Morrell NW, Yang X, Upton PD, Jourdan KB, Morgan N, Sheares KK et al (2001) Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-β1 and bone morphogenetic proteins. Circulation 104:790–795

    PubMed  CAS  Google Scholar 

  140. Zhang S, Fantozzi I, Tigno DD, Yi ES, Platoshyn O, Thistlethwaite PA et al (2003) Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 285:L740–L754

    PubMed  CAS  Google Scholar 

  141. Yang XD, Long L, Southwood M, Rudarakanchana N, Upton PD, Jeffery TK et al (2005) Dysfunctional smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res 96:1053–1063

    PubMed  CAS  Google Scholar 

  142. Jeffery TK, Upton PD, Trembath RC, Morrell NW (2005) BMP4 inhibits proliferation and promotes myocyte differentiation of lung fibroblasts via Smad1 and JNK pathways. Am J Physiol Lung Cell Mol Physiol 288:L370–L378

    PubMed  CAS  Google Scholar 

  143. Teichert-Kuliszewska K, Kutryk MJB, Kuliszewski MA, Karoubi G, Courtman DW, Zucco L et al (2006) Bone morphogenetic protein receptor-2 signaling promotes pulmonary arterial endothelial cell survival: implications for loss-of-function mutations in the pathogenesis of pulmonary hypertension. Circ Res 98:209–217

    PubMed  CAS  Google Scholar 

  144. Attisano L, Wrana JL (2002) Signal transduction by the TGF-β superfamily. Science 296:1646–1647

    PubMed  CAS  Google Scholar 

  145. Morrell NW (2006) Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling? Proc Am Thorac Soc 3:680–686

    PubMed  CAS  Google Scholar 

  146. Atkinson C, Stewart S, Upton PD, Machado R, Thomson JR, Trembath RC et al (2002) Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 105:1672–1678

    PubMed  CAS  Google Scholar 

  147. Eickelberg O, Morty RE (2007) Transforming growth factor β/bone morphogenic protein signaling in pulmonary arterial hypertension: remodeling revisited. Trends Cardiovasc Med 17:263–269

    PubMed  CAS  Google Scholar 

  148. Masri FA, Xu W, Comhair SAA, Asosingh K, Koo M, Vasanji A et al (2007) Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 293:L548–L554

    PubMed  CAS  Google Scholar 

  149. Long L, MacLean MR, Jeffery TK, Morecroft I, Yang XD, Rudarakanchana N et al (2006) Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circ Res 98:818–827

    PubMed  CAS  Google Scholar 

  150. West J, Cogan J, Geraci M, Robinson L, Newman J, Phillips JA et al (2008) Gene expression in BMPR2 mutation carriers with and without evidence of pulmonary arterial hypertension suggests pathways relevant to disease penetrance. BMC Med Genomics 1:45

    PubMed  Google Scholar 

  151. Moudgil R, Michelakis ED, Archer SL (2006) The role of K+ channels in determining pulmonary vascular tone, oxygen sensing, cell proliferation, and apoptosis: implications in hypoxic pulmonary vasoconstriction and pulmonary arterial hypertension. Microcirculation 13:615–632

    PubMed  CAS  Google Scholar 

  152. Burg ED, Remillard CV, Yuan JX-J (2008) Potassium channels in the regulation of pulmonary artery smooth muscle cell proliferation and apoptosis: pharmacotherapeutic implications. Br J Pharmacol 153:S99–S111

    PubMed  CAS  Google Scholar 

  153. Gurney AM, Osipenko ON, MacMillan D, McFarlane KM, Tate RJ, Kempsill FEJ (2003) Two-pore domain K channel, TASK-1, in pulmonary artery smooth muscle cells. Circ Res 93:957–964

    PubMed  CAS  Google Scholar 

  154. Olschewski A, Li Y, Tang B, Hanze J, Eul B, Bohle RM et al (2006) Impact of TASK-1 in human pulmonary artery smooth muscle cells. Circ Res 98:1072–1080

    PubMed  CAS  Google Scholar 

  155. Archer SL, Huang JMC, Reeve HL, Hampl V, Tolarova S, Michelakis E et al (1996) Differential distribution of electrophysiologically distinct myocytes in conduit and resistance arteries determines their response to nitric oxide and hypoxia. Circ Res 78:431–442

    PubMed  CAS  Google Scholar 

  156. Moudgil R, Michelakis ED, Archer SL (2005) Hypoxic pulmonary vasoconstriction. J Appl Physiol 98:390–403

    PubMed  CAS  Google Scholar 

  157. Silvani P, Camporesi A (2007) Drug-induced pulmonary hypertension in newborns: a review. Curr Vasc Pharmacol 5:129–133

    PubMed  CAS  Google Scholar 

  158. MacLean MR, Herve P, Eddahibi S, Adnot S (2000) 5-Hydroxytryptamine and the pulmonary circulation: receptors, transporters and relevance to pulmonary arterial hypertension. Br J Pharmacol 131:161–168

    PubMed  CAS  Google Scholar 

  159. Madden JA, Vadula MS, Kurup VP (1992) Effects of hypoxia and other vasoactive agents on pulmonary and cerebral artery smooth muscle cells. Am J Physiol 263:L384–L393

    PubMed  CAS  Google Scholar 

  160. Michelakis ED, Thebaud B, Weir EK, Archer SL (2004) Hypoxic pulmonary vasoconstriction: redox regulation of O2-sensitive K+ channels by a mitochondrial O2-sensor in resistance artery smooth muscle cells. J Mol Cell Cardiol 37:1119–1136

    PubMed  CAS  Google Scholar 

  161. Cornfield DN, Reeve HL, Tolarova S, Weir EK, Archer S (1996) Oxygen causes fetal pulmonary vasodilation through activation of a calcium-dependent potassium channel. Proc Natl Acad Sci U S A 93:8089–8094

    PubMed  CAS  Google Scholar 

  162. Archer SL, Wu XC, Thebaud B, Nsair A, Bonnet S, Tyrrell B et al (2004) Preferential expression and function of voltage-gated, O2-sensitive K+ channels in resistance pulmonary arteries explains regional heterogeneity in hypoxic pulmonary vasoconstriction: ionic diversity in smooth muscle cells. Circ Res 95:308–318

    PubMed  CAS  Google Scholar 

  163. Pozeg ZI, Michelakis ED, McMurtry MS, Thebaud B, Wu XC, Dyck JRB et al (2003) In vivo gene transfer of the O2-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats. Circulation 107:2037–2044

    PubMed  CAS  Google Scholar 

  164. Gurney A, Manoury B (2008) Two-pore potassium channels in the cardiovascular system. Eur Biophys J 38(3):305–318

    PubMed  Google Scholar 

  165. Weir EK, Obreztchikova M, Vargese A, Cabrera JA, Peterson DA, Hong Z (2008) Mechanisms of oxygen sensing: a key to therapy of pulmonary hypertension and patent ductus arteriosus. Br J Pharmacol 155:300–307

    PubMed  CAS  Google Scholar 

  166. Platoshyn O, Golovina VA, Bailey CL, Limsuwan A, Krick S, Juhaszova M et al (2000) Sustained membrane depolarization and pulmonary artery smooth muscle cell proliferation. Am J Physiol Cell Physiol 279:C1540–C1549

    PubMed  CAS  Google Scholar 

  167. Yuan JX-J, Aldinger AM, Juhaszova M, Wang J, Conte JV Jr, Gaine SP et al (1998) Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 98:1400–1406

    PubMed  CAS  Google Scholar 

  168. Yuan XJ, Wang J, Juhaszova M, Gaine SP, Rubin LJ (1998) Attenuated K+ channel gene transcription in primary pulmonary hypertension. Lancet 351:726–727

    PubMed  CAS  Google Scholar 

  169. McMurtry MS, Bonnet S, Wu X, Dyck JRB, Haromy A, Hashimoto K et al (2004) Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 95:830–840

    PubMed  CAS  Google Scholar 

  170. Ross R, Glomset J, Kariya B, Harker L (1974) A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci U S A 71:1207–1210

    PubMed  CAS  Google Scholar 

  171. Kohler N, Lipton A (1974) Platelets as a source of fibroblast growth-promoting activity. Exp Cell Res 87:297–301

    PubMed  CAS  Google Scholar 

  172. Heldin CH, Westermark B, Wasteson A (1979) Platelet-derived growth factor: purification and partial characterization. Proc Natl Acad Sci U S A 76:3722–3726

    PubMed  CAS  Google Scholar 

  173. Raines EW (2004) PDGF and cardiovascular disease. Cytokine Growth Factor Rev 15:237–254

    PubMed  CAS  Google Scholar 

  174. Li X, Ponten A, Aase K, Karlsson L, Abramsson A, Uutela M et al (2000) PDGF-C is a new protease-activated ligand for the PDGF α-receptor. Nat Cell Biol 2:302–309

    PubMed  CAS  Google Scholar 

  175. Bergsten E, Uutela M, Li X, Pietras K, Ostman A, Heldin CH et al (2001) PDGF-D is a specific, protease-activated ligand for the PDGF β-receptor. Nat Cell Biol 3:512–516

    PubMed  CAS  Google Scholar 

  176. LaRochelle WJ, Jeffers M, McDonald WF, Chillakuru RA, Giese NA, Lokker NA et al (2001) PDGF-D, a new protease-activated growth factor. Nat Cell Biol 3:517–521

    PubMed  CAS  Google Scholar 

  177. Perros F, Montani D, Dorfmuller P, Durand-Gasselin I, Tcherakian C, Le Pavec J et al (2008) Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 178:81–88

    PubMed  CAS  Google Scholar 

  178. Balasubramaniam V, Le Cras TD, Ivy DD, Grover TR, Kinsella JP, Abman SH (2003) Role of platelet-derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus. Am J Physiol Lung Cell Mol Physiol 284:L826–L833

    PubMed  CAS  Google Scholar 

  179. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M et al (2005) Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 115:2811–2821

    PubMed  CAS  Google Scholar 

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  1. Mandy MacLean College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ, Glasgow, UK

    Margaret R. MacLean

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  1. Margaret R. MacLean
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  2. Yvonne Dempsie
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Correspondence to Margaret R. MacLean .

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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

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MacLean, M.R., Dempsie, Y. (2011). The Influence of the Major Vasoactive Mediators Relevant to the Pathogenesis of Pulmonary Hypertension. 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_8

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