Pulmonary hypertension: From molecular pathophysiology to haemodynamic abnormalities;Hypertension pulmonaire : De la physiopathologie moléculaire aux anomalies hémodynamiques

Revue des Maladies Respiratoires

Volumn 29, Issue 8, 2012, Pages 956-970

  Duong Quy, S ^a   Riviere S ^a   Bei, Y ^a   Duong Ngo, C ^a   Le Dong, N N ^a   Hua Huy, T ^a   Dinh Xuan, A T ^a  

^a Institut Cochin   (France)

Author keywords

Haemodynamic; Molecular pathology; Physiopathology; Pulmonary arterial hypertension; Pulmonary hypertension

Indexed keywords

ARTICLE; LUNG HEMODYNAMICS; MOLECULAR PATHOLOGY; PULMONARY HYPERTENSION;

EID: 84873131167     PISSN: 07618425     EISSN: 17762588     Source Type: Journal    
DOI: 10.1016/j.rmr.2012.03.009     Document Type: Review

References (150)

1. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: Prognostic factors and survival. J Am Coll Cardiol 2002;40:780 - 8.
2. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009;30:2493 - 537.
3. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009;34:1219 - 63.
4. Aaronson PI, Robertson TP, Knock GA, et al. Hypoxic pulmonary vasoconstriction: Mechanisms and controversies. J Physiol 2006;570:53 - 8.
5. Brimioulle S, LeJeune P, Naeije R. Effects of hypoxic pulmonary vasoconstriction on pulmonary gas exchange. J Appl Physiol 1996;81:1535 - 43.
6. Kovacs G, Berghold A, Scheidl S, et al. Pulmonary arterial pressure during rest and exercise in healthy subjects. A systematic review. Eur Respir J 2009;4:888 - 94.
7. Sommer N, Dietrich A, Schermuly RT, et al. Regulation of hypoxic pulmonary vasoconstriction: Basic mechanisms. Eur espir J 2008;32:1639 - 51.
8. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004;109:159 - 65.
9. Montani D, Price LC, Dorfmuller P, et al. Pulmonary venoocclusive disease. Eur Respir J 2009;33:189 - 200.
10. Hayashi K, Handa H, Nagasawa S, et al. Stiffness and elastic behavior of human intracranial and extracranial arteries. J Biomech 1980;13:175 - 84.
11. Gan CT, Lankhaar JW, Westerhof N, et al. Noninvasively assessed pulmonary artery stiffness predicts mortality in pulmonary arterial hypertension. Chest 2007;132:1906 - 12.
12. Badesch BD, Champion HC, Gomez-Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S55 - 6.
13. Oudiz RJ. Pulmonary hypertension associated with left-sided heart disease. Clin Chest Med 2007;28:233 - 41.
14. Dinh-Xuan AT, Duong-Quy S. New international guidelines on pulmonary hypertension. Rev Mal Respir 2010;27:110 - 1.
15. Moncada S, Palmer RM, Higgs EA. Biosynthesis of nitric oxide from L-arginine: A pathway for the regulation of cell function and communication. Biochem Pharmacol 1989;38: 1709 - 15.
16. Emerson M, Momi S, Paul W, et al. Endogenous nitric oxide acts as a natural antithrombotic agent in vivo by inhibiting platelet aggregation in the pulmonary vasculature. Thromb Haemost 1999;81:961 - 6.
17. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333:214 - 21.
18. Xue C, Johns RA. Endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333:1642 - 4.
19. Demoncheaux EA, Higenbottam TW, Kiely DG, et al. Decreased whole body endogenous nitric oxide production in patients with primary pulmonary hypertension. J Vasc Res 2005;42:133 - 6.
20. Kielstein JT, Bode-Böger SM, Hesse G, et al. Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 2005;25:1414 - 8.
21. Stamler JS, Lamas S, Fang FC. Nitrosylation. The prototypic redox-based signaling mechanism. Cell 2001;106:675 - 83.
22. Laufs U, Endres M, Liao JK. Regulation of endothelial NO production by Rho GTPase. Med Klin 1999;94:211 - 8.
23. Thusu KG, Morin FC, Russel JA, et al. The cGMP phosphodiesterase inhibitor Zaprinast enhances the effect of nitric oxide. Am J Respir Crit Care Med 1995;152:1605 - 10.
24. Prasad S, Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary hypertension. N Engl J Med 2000;343:1342.
25. Ghofrani HA, Hoeper MM, Halank M, et al. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: A phase II study. Eur Respir J 2010;36:792 - 9.
26. Tuder RM, Zaiman AL. Prostacyclin analogs as the brakes for pulmonary artery smooth muscle cell proliferation: Is it sufficient to treat severe pulmonary hypertension? Am J Respir Cell Mol Biol 2002;26:171 - 4.
27. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999;159:1925 - 32.
28. Geraci MW, Gao B, Shepherd DC, et al. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. J Clin Invest 1999;103:1509 - 15.
29. Hoshikawa Y, Voelkel NF, Gesell TL, et al. Prostacyclin receptor-dependent modulation of pulmonary vascular remodeling. Am J Respir Crit Care Med 2001;164:314 - 8.
30. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: The impact of epoprostenol therapy. Circulation 2002;106:1477 - 82.
31. Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992;327:70 - 5.
32. Katugampola SD, Davenport AP. Thromboxane receptor density is increased in human cardiovascular disease with evidence for inhibition at therapeutic concentrations by the AT(1) receptor antagonist losartan. Br J Pharmacol 2001;134:1385 - 92.
33. Dao P, Montani D, Duong-Quy S, et al. Signalisation cellulaire et physiopathologie de l'hypertension artérielle pulmonaire. Rev Mal Respir 2006;23:3S75 - 83S.
34. Dinh-Xuan AT. Endothelial modulation of pulmonary vascular tone. Eur Respir J 1992;5:757 - 62.
35. Masaki T, Miwa S, Sawamura T, et al. Subcellular mechanisms of endothelin action in vascular system. Eur J Pharmacol 1999;375:133 - 8.
36. Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in pulmonary hypertension: Marker or mediator of disease? Ann Intern Med 1991;114:464 - 9.
37. Galie N, Grigioni F, Bacchi-Reggiani L. Relation of endothelin- 1 to survival in patients with primary pulmonary hypertension. Eur J Clin Invest 1996;26:273.
38. Cacoub P, Dorent R, Maistre G, et al. Endothelin-1 in primary pulmonary hypertension and the Eisenmenger syndrome. Am J Cardiol 1993;71:448 - 50.
39. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732 - 9.
40. MacLean MR, Hervé P, Eddahibi S, et al. 5-hydroxytryptamine and the pulmonary circulation: Receptors, transpoters and relevance to pulmonary arterial hypertension. Br J Pharmacol 2000;131:161 - 8.
41. Song D, Wang HL, Wang S, et al. 5-Hydroxytryptamine-induced proliferation of pulmonary artery smooth muscle cells are extracellular signal-regulated kinase pathway dependent. Acta Pharmacol Sin 2005;26:563 - 7.
42. Eddahibi S, Humbert M, Fadel E, et al. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 2001;108:1141 - 50.
43. Izikki M, Hanoun N, Marcos E, et al. Tryptophan hydroxylase 1 (Tph1) knock-out and Tph2 polymorphism: Effects on hypoxic pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol 2007;293:L1045 - 52.
44. MacLean MR, Deuchar GA, Hicks MN, et al. Overexpression of the 5-hydroxytryptamine transporter gene - effect on pulmonary hemodynamics and hypoxiainduced pulmonary hypertension. Circulation 2004;109: 2150 - 5.
45. Guignabert C, Izikki M, Tu LI, et al. Transgenic mice overexpressing the 5-hydroxytryptamine transporter gene in smooth muscle develop pulmonary hypertension. Circ Res 2006;98:1323 - 30.
46. Marcos E, Adnot S, Pham MH, et al. Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension. Am J Respir Crit Care Med 2003;168:487 - 93.
47. Guignabert C, Raffestin B, Benferhat R, et al. Serotonin transporter inhibition prevents and reverses monocrotalineinduced pulmonary hypertension in rats. Circulation 2005;111:2812 - 9.
48. Rothman RB, Ayestas MA, Dersch CM, et al. Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates-Implications for primary pulmonary hypertension. Circulation 1999;100:869 - 75.
49. Eddahibi S, Guignabert C, Barlier-Mur AM, et al. Cross-talk between endothelial and smooth muscle cells in pulmonary hypertension: Critical role for serotonin-induced smooth muscle hyperplasia. Circulation 2006;113:1857 - 64.
50. Morecroft I, Dempsie Y, Bader M, et al. Effect of tryptophan hydroxylase 1 deficiency on the development of hypoxia-induced pulmonary hypertension. Hypertension 2007;49:232 - 6.
51. Dempsie Y, Morecroft I, Welsh DJ, et al. Converging evidence in support of the serotonin hypothesis of dexfenfluramineinduced pulmonary hypertension with novel transgenic mice. Circulation 2008;117:2928 - 37.
52. Hervé P, Humbert M, Sitbon O, et al. Pathobiology of pulmonary hypertension: The role of platelets and thrombosis. Clin Chest Med 2001;22:451 - 8.
53. Morecroft I, Heeley RP, Prentice HM, et al. 5- hydroxytryptamine receptors mediating contraction in human small muscular pulmonary arteries: Importance of the 5-HT1B receptor. Br J Pharmacol 1999;128:730 - 4.
54. Launay JM, Hervé P, Peoc'h K, et al. Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat Med 2002;8:1129 - 35.
55. Long L, MacLean MR, Jeffery TK, et al. Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circ Res 2006;98:818 - 27.
56. Jovanovic A, Jovanovic S, Tulic I, et al. Predominant role for nitric oxide in the relaxation induced by vasoactive intestinal polypeptide in human uterine artery. Mol Hum Reprod 1998;4:71 - 6.
57. Petkov V, Mosgoeller W, Ziesche R, et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest 2003;111:1339 - 46.
58. Said SI, Hamidi SA, Dickman KG, et al. Moderate pulmonary arterial hypertension in male mice lacking the vasoactive intestinal peptide gene. Circulation 2007;115:1260 - 8.
59. Haberl I, Frei K, Ramsebner R, et al. Vasoactive intestinal peptide gene alterations in patients with idiopathic pulmonary arterial hypertension. Eur J Hum Genet 2007;15:18 - 22.
60. Dey RD, Shannon Jr WA, Said SI. Localization of VIPimmunoreactive nerves in airways and pulmonary vessels of dogs, cat, and human subjects. Cell Tissue Res 1981;220:231 - 8.
61. Leuchte HH, Baezner C, Baumgartner RA, et al. Inhalation of vasoactive intestinal peptide in pulmonary hypertension. Eur Respir J 2008;32:1289 - 94.
62. Post JM, Hume JR, Archer SL, et al. Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction. Am J Physiol 1992;262:C882 - 90.
63. Yuan JX, Aldinger AM, Juhaszova M, et al. Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 1998;98:1400 - 6.
64. Weir EK, Reeve HL, Huang JMC, et al. The anorexic agents aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in rat pulmonary vascular smooth muscle and cause pulmonary vasoconstriction. Circulation 1996;94:2216 - 20.
65. Pozeg ZI, Michelakis ED, McMurtry MS, et al. 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 2003;107:2037 - 44.
66. Young KA, Ivester C, West J, et al. BMP signaling controls PASMC KV channel expression in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol 2006;290:L841 - 8.
67. Nagaoka T, Gebb SA, Karoor V, et al. Involvement of RhoA/Rho-kinase signaling in pulmonary hypertension of the fawn-hooded rat. J Appl Physiol 2006;100:996 - 1002.
68. Homma N, Nagaoka T, Karoor V, et al. Involvement of RhoA/Rho-kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized rats by dehydroepiandrosterone. Am J Physiol Lung Cell Mol Physiol 2008;295:71 - 8.
69. Loirand G, Guérin P, Pacaud P. Rho-kinases in cardiovascular physiology and pathophysiology. Circ Res 2006;98:322 - 34.
70. Schwenke DO, Pearson JT, Sonobe T, et al. Role of Rho-kinase signaling and endothelial dysfunction in modulating blood flow distribution in pulmonary hypertension. J Appl Physiol 2011;110:901 - 8.
71. Homma N, Nagaoka T, Morio Y, et al. Endothelin-1 and serotonin are involved in activation of RhoA/Rho-kinase signaling in the chronically hypoxic hypertensive rat pulmonary circulation. J Cardiovasc Pharmacol 2007;50:697 - 702.
72. Guilluy C, Rolli-Derkinderen M, Tharaux PL, et al. Transglutaminase- dependent rhoa activation and depletion by serotonin in vascular smooth muscle cells. J Biol Chem 2007;282:2918 - 28.
73. Hernández-Perera O, Pérez-Sala D, Soria E, et al. Involvement of Rho GTPases in the transcriptional inhibition of preproendothelin-1 gene expression by simvastatin in vascular endothelial cells. Circ Res 2000;87:616 - 22.
74. Guilluy C, Eddahibi S, Agard C, et al. RhoA and Rho-kinase activation in human pulmonary hypertension: Role of 5-HT signaling. Am J Respir Crit Care Med 2009;179:1151 - 8.
75. Abe K, Uwatoku T, Oi K, et al. Long-term inhibition of rhokinase ameliorates hypoxia-induced pulmonary hypertension in mice independent of endothelial NO synthase. Circulation 2003;108:1399 - 400.
76. Abe K, Shimokawa H, Morikawa K, et al. Long-term treatment with a Rho-kinase inhibitor improves monocrotalineinduced fatal pulmonary hypertension in rats. Circ Res 2004;94:385 - 93.
77. Fukumoto Y, Matoba T, Ito A, et al. Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart 2005;91:391 - 2.
78. Ishikura K, Yamada N, Ito M, et al. Beneficial acute effects of Rho-kinase inhibitor in patients with pulmonary arterial hypertension. Circ J 2006;70:174 - 8.
79. Li F, Xia W, Yuan S, et al. Acute inhibition of Rho-kinase attenuates pulmonary hypertension in patients with congenital heart disease. Pediatr Cardiol 2009;30:363 - 6.
80. Fujita H, Fukumoto Y, Saji K, et al. Acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor, in patients with pulmonary arterial hypertension. Heart Vessels 2010;25:144 - 9.
81. Miyazono K, Kusanagi K, Inoue H. Divergence and convergence of TGF-̈/BMP signaling. J Cell Physiol 2001;187:265 - 76.
82. Massague J, Seoane J, Wotton D. Smad transcription factors. Genes Dev 2005;19:2783 - 810.
83. Teichert-Kuliszewska K, Kutryk MJB, Kuliszewski MA, et al. 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 2006;98:209 - 17.
84. Loyd JE, Primm RK, Newmann JH. Transmission of familial primary pulmonary hypertension. Am Rev Respir Dis 1984;129:194 - 7.
85. Sztrymf B, Coulet F, Girerd B, et al. Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med 2008;177:1377 - 83.
86. Rosenzweig EB, Morse JH, Knowles JA, et al. Clinical implications of determining BMPR2 mutation status in a large cohort of children and adults with pulmonary arterial hypertension. J Heart Lung Transplant 2008;27:668 - 74.
87. Girerd B, Montani D, Coulet F, et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 2010;181: 851 - 61.
88. Lane KB, Machado RD, Pauciulo MW, et al. Heterzygous germline mutations in BMPR II, encoding a TGF-̈ receptor, cause familial primary hypertension. Nat Genet 2000;67: 737 - 44.
89. Machado RD, Pauciulo MW, Thomson JR, et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet 2001;68:92 - 102.
90. Koehler R, Grunig E, PauciuloMW, et al. Low frequency of BMPR2 mutations in a German cohort of patients with sporadic idiopathic pulmonary arterial hypertension. J Med Genet 2004;41:e127.
91. Morisaki H, Nakanishi N, Kyotani S, et al. BMPR2 mutations found in Japanese patients with familial and sporadic primary pulmonary hypertension. Hum Mutat 2004;23:632.
92. Elliott CG. Genetics of pulmonary arterial hypertension: Current and future implications. Semin Respir Crit Care Med 2005;26:365 - 71.
93. Roberts KE, Barst RJ, McElroy JJ, et al. Bone morphogenetic protein receptor-2 mutations in adults and children with idiopathic pulmonary arterial hypertension association with thyroid disease. Chest 2005;128:618S.
94. Abramowicz MJ, Van Haecke P, Demedtsz M, et al. Primary pulmonary hypertension after amfepramone (diethylpropion) with BMPR2 mutation. Eur Respir J 2003;22:560 - 2.
95. Humbert M, Deng Z, Simonneau G, et al. BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur Respir J 2002;20:518 - 23.
96. Souza R, Humbert M, Sztrymf B, et al. Pulmonary arterial hypertension associated with fenfluramine exposure: Report of 109 cases. Eur Respir J 2008;31:343 - 8.
97. Roberts KE, McElroy JJ, Wong WPK, et al. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J 2004;24:371 - 4.
98. Atkinson C, Stewart S, Upton PD, et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 2002;105:1672 - 8.
99. Fantozzi I, Huang W, Zhang J, et al. Divergent effects of BMP- 2 on gene expression in pulmonary artery smooth muscle cells from normal subjects and patients with idiopathic pulmonary arterial hypertension. Exp Lung Res 2005;31:783 - 806.
100. Hagen M, Fagan K, Steudel W, et al. Interaction of interleukin- 6 and the BMP pathway in pulmonary smooth muscle. Am J Physiol Lung Cell Mol Physiol 2007;292:L1473 - 9.
101. Kohno M, Pouyssegur J. Pharmacological inhibitors of the ERK signaling pathway: Application as anticancer drugs. Prog Cell Cycle Res 2003;5:219 - 24.
102. He H, Venema VJ, Gu X, et al. Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. J Biol Chem 1999;274:25130 - 5.
103. Tuder RM, Chacon M, Alger L, et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: Evidence for a process of disordered angiogenesis. J Pathol 2001;195:367 - 74.
104. Niimi H, Arimura K, Jonosono M, et al. VEGF is causative for pulmonary hypertension in a patient with Crow-Fukase (POEMS) syndrome. Intern Med 2000;39:1101 - 4.
105. Cool CD, Rai PR, Yeager ME, et al. Expression of human herpes virus 8 in primary pulmonary hypertension. N Engl J Med 2003;349:1113 - 22.
106. Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115:2811 - 21.
107. Balasubramaniam V, Le Cras TD, Ivy DD, et al. Role of platelet-derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus. Am J Physiol Lung Cell Mol Physiol 2003;284:L826 - 33.
108. Ghofrani HA, Morrell NW, Hoeper MM, et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med 2010;182:1171 - 7.
109. Zakrzewicz A, Kouri FM, Nejman B, et al. The transforming growth factor-beta/Smad2, 3 signalling axis is impaired in experimental pulmonary hypertension. Eur Respir J 2007;29:1094 - 104.
110. Jinnin M, Ihn H, Tamaki K. Characterization of SIS3, a novel specific inhibitor of smad3 and its effects on transforming growth factor-1-induced extracellular matrix expression. Mol Pharmacol 2006;69:597 - 607.
111. Merklinger SL, Jones PL, Martinez EC, et al. Epidermal growth factor receptor blockade mediates smooth muscle cellapoptosis and improves survival in rats with pulmonary hypertension. Circulation 2005;112:423 - 31.
112. Schumann C, Lepper PM, Frank H, et al. Circulating biomarkers f tissue remodelling in pulmonary hypertension. Biomarkers 2010;15:523 - 32.
113. Jones PL, Rabinovitch M. Tenascin-C is induced with progressive pulmonary vascular disease in rats and is functionally related to increased smooth muscle cell proliferation. Circ Res 1996;79:1131 - 42.
114. Jones PL, Cowan KN, Rabinovitch M. Tenascin-C, proliferation and subendothelial fibronectin in progressive pulmonary vascular disease. Am J Pathol 1997;150:1349 - 60.
115. Ihida-Stansbury K, McKean DM, Lane KB, et al. Tenascin-C is induced by mutated BMP type II receptors in familial forms of pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2006;291:L694 - 702.
116. Jones PL, Crack J, Rabinovitch M. Regulation of tenascin-C, a vascular smooth muscle cell survival factor that interacts with the alpha v beta 3 integrin to promote epidermal growth factor receptor phosphorylation and growth. J Cell Biol 1997;139:279 - 93.
117. Cowan KN, Jones PL, Rabinovitch M. Regression of hypertrophied rat pulmonary arteries in organ culture is associated with suppression of proteolytic activity, inhibition of tenascin-C, and smooth muscle cell apoptosis. Circ Res 1999;84:1223 - 33.
118. Cowan KN, Heilbut A, Humpl T, et al. Complete reversal of fatal pulmonary hypertension in rats by a serine élastase inhibitor. Nat Med 2000;6:698 - 702.
119. Zaidi SH, You XM, Ciura S, et al. Overexpression ofthe serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension. Circulation 2002;105:516 - 21.
120. Umar S, Hessel M, Steendijk P, et al. Activation of signaling molecules and matrix metalloproteinases in right ventricular myocardium of rats with pulmonary hypertension. Pathol Res Pract 2007;203:863 - 72.
121. Lepetit H, Eddahibi S, Fadel E, et al. Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension. Eur Respir J 2005;25:834 - 42.
122. Voelkel NF, Cool C, Lee SD, et al. Primary pulmonary hypertension between inflammation and cancer. Chest 1998;114:225S - 30S.
123. Tuder RM, Voelkel NF. Pulmonary hypertension and inflammation. J Lab Clin Med 1998;132:16 - 24.
124. Dorfmüller P, Perros F, Balabanian K, et al. Inflammation in pulmonary arterial hypertension. Eur Respir J 2003;22:358 - 63.
125. Tamby MC, Chanseaud Y, Humbert M, et al. Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax 2005;60:765 - 72.
126. Isern RA, Yaneva M, Weiner E, et al. Autoantibodies in patients with primary pulmonary hypertension: Association with anti- Ku. Am J Med 1992;93:307 - 12.
127. Tuder RM, Groves B, Badesch DB, et al. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 1994;144:275 - 85.
128. Pietra GG, Capron F, Stewart S, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol 2004;43:25S - 32S.
129. Perros F, Dorfmüller P, Souza R, et al. Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension. Eur Respir J 2007;29:462 - 8.
130. Humbert M, Monti G, Brenot F, et al. Increased interleukin- 1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 1995;151:1628 - 31.
131. Steiner MK, Syrkina OL, Kolliputi N, et al. Interleukin- 6 overexpression induces pulmonary hypertension. Cir Res 2009;104:236 - 44.
132. Furuya Y, Satoh T, Kuwana M. Interleukin-6 as a potential therapeutic target for pulmonary arterial hypertension. Int J Rheumatol 2010;2010:720305.
133. Balabanian K, Foussat A, Dorfmüller P, et al. CX3C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med 2002;165:1419 - 25.
134. Perros F, Dorfmüller P, Souza R, et al. Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension. Eur Respir J 2007;29:937 - 43.
135. Sanchez O, Marcos E, Perros F, et al. Role of endotheliumderived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2007;176:1041 - 7.
136. Sullivan CC, Du L, Chu D, et al. Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway. Proc Natl Acad Sci U S A 2003;100:12331 - 6.
137. Dewachter L, Adnot S, Fadel E, et al. Angiopoietin/ Tie2 pathway influences smooth muscle hyperplasia in idiopathic pulmonary hypertension. Am J Respir Crit Care Med 2006;174:1025 - 33.
138. Machado RD, Aldred MA, James V, et al. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 2006;27:121 - 32.
139. Doe Z, Fukumoto Y, Takaki A, et al. Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension. Circ J 2009;73:1731 - 9.
140. Speich R, Jenni R, Opravil M, et al. Primary pulmonary hypertension in HIV infection. Chest 1991;100:1268 - 71.
141. Mette SA, Palevsky HI, Pietra GG, et al. Primary pulmonary hypertension in association with human immunodeficiency virus infection. A possible viral etiology for some forms of hypertensive pulmonary arteriopathy. Am Rev Respir Dis 992;145:1196 - 200.
142. Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med 2008;177:108 - 13.
143. Bull TM, Cool CD, Serls AE, et al. Primary pulmonary hypertension. Castleman's disease and human herpesvirus-8. Eur Respir J 2003;22:403 - 7.
144. Montani D, Marcelin AG, Sitbon O, et al. Human herpes virus 8 in HIV and non-HIV infected patients with pulmonary arterial hypertension in France. AIDS 2005;19:1239 - 40.
145. Spiekerkoetter E, Alvira CM, Kim YM, et al. Reactivation of gammaHV68 induces neointimal lesions in pulmonary arteries of S100A4/Mts1-overexpressing mice in association with degradation of elastin. Am J Physiol Lung Cell Mol Physiol 2008;294:L276 - 89.
146. Shan B, Morris CA, Zhuo Y, et al. Activation of proMMP-2 and Src by HHV-8 vGPCR in human pulmonary arterial endothelial cells. J Mol Cell Cardiol 2007;42:517 - 25.
147. Valmary S, Dorfmüller P, Montani D, et al. Human gammaherpesviruses EBV and HHV-8 are not detected in the lungs of patients with severe pulmonary arterial hypertension. Chest 2011;139:1310 - 6.
148. Bull TM, Meadows CA, Coldren CD, et al. Human herpesvirus- 8 infection of primary pulmonary microvascular endothelial cells. Am J Respir Cell Mol Biol 2008;39:706 - 16.
149. Moorman J, Saad M, Kosseifi S, et al. Hepatitis C virus and the lung: Implications for therapy. Chest 2005;128: 2882 - 92.
150. Robalino BD, Moodie DS. Association between primary pulmonary hypertension and portal hypertension: Analysis of its pathophysiology and clinical, laboratory and hemodynamicmanifestations. J Am Coll Cardiol 1991;17:492 - 8.