A comprehensive review: The evolution of animal models in pulmonary hypertension research; are we there yet?

Pulmonary Circulation

Volumn 3, Issue 4, 2013, Pages 739-756

  Maarman, Gerald ^a   Lecour, Sandrine ^a   Butrous, Ghazwan ^b   Thienemann, Friedrich ^a   Sliwa, Karen ^a  

^a UNIVERSITY OF CAPE TOWN   (South Africa)

^b UNIVERSITY OF KENT   (United Kingdom)

Author keywords

Chronic hypoxia; Monocrotaline; Pulmonary arterial banding; Right ventricular failure

Indexed keywords

EID: 84922278682     PISSN: 20458932     EISSN: 20458940     Source Type: Journal    
DOI: 10.1086/674770     Document Type: Review

References (186)

1. Badesch BD, Champion HC, Gomez-Sanchez MA, Hoeper M, Loyd J, Manes A, McGoon MD, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54(suppl.):S55-S56.
2. Simonneau G. A new clinical classification of pulmonary hypertension. Bull Acad Natl Med 2009;193:794-804 (in French with English abstract).
3. Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest 2009;135:794-804.
4. Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, Dupuis J, et al. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation 2006;114: 1883-1891.
5. Rich S. The importance of sex in pulmonary hypertension. Chest 2012;141:4-5.
6. Gabler NB, French B, Strom BL, Liu Z, Palevsky HI, Taichman DB, Kawut SM, Halpern SD. Race and sex differences in response to endothelin receptor antagonists for pulmonary arterial hypertension. Chest 2012;141:20-26.
7. Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216-223.
8. Sztrymf B, Souza R, Bertoletti L, Jais X, Sitbon O, Price LC, Simonneau G, Humbert M. Prognostic factors of acute heart failure in patients with pulmonary arterial hypertension. Eur Respir J 2010;35:1286-1293.
9. Gomberg-Maitland M, Dufton C, Oudiz RJ, Benza RL. Compelling evidence of long-term outcomes in pulmonary arterial hypertension? J Am Coll Cardiol 2011;57:1053-1061.
10. Essop MR. Contemporary insights into the pathogenesis, diagnosis and therapy of pulmonary arterial hypertension. Cardiovasc J Afr 2010;21:334-337.
11. Rich S, Pogoriler J, Husain AN, Toth PT, Gomberg- Maitland M, Archer SL. Long-term effects of epoprostenol on the pulmonary vasculature in idiopathic pulmonary arterial hypertension. Chest 2010;138(5):1234-1239.
12. O’Callaghan DS, Humbert M. A critical analysis of survival in pulmonary arterial hypertension. Eur Respir Rev 2012;21(125):218-222.
13. Andersen CU, Mellemkjaer S, Hilberg O, Nielsen-Kudsk JE, Simonsen U, Bendstrup E. Pulmonary hypertension in interstitial lung disease: prevalence, prognosis and 6 min walk test. Respir Med 2012;106:875-882.
14. Argiento P, Vanderpool RR, Mule M, Russo MG, D’Alto M, Bossone E, Chesler NC, Naeije R. Exercise stress echocardiography of the pulmonary circulation: limits of normal and gender differences. Chest 2012;142(5):1158-1165.
15. van der Laarse A, Steendijk P, van der Wall EE. Evaluation of pulmonary arterial hypertension: invasive or noninvasive? Int J Cardiovasc Imaging 2011;27:943-945.
16. Agarwal R. Prevalence, determinants and prognosis of pulmonary hypertension among hemodialysis patients. Nephrol Dial Transplant 2012;27(10):3908-3914.
17. Benisty JI. Pulmonary hypertension. Circulation 2002;106: e192-e194.
18. Kay JM. Dietary pulmonary hypertension. Thorax 1994;49: S33-S38.
19. Heath D, Shaba J, Williams A, Smith P, Kombe A. A pulmonary hypertension-producing plant from Tanzania. Thorax 1975;30:399-404.
20. Kay JM, Harris P, Heath D. Pulmonary hypertension produced in rats by ingestion of Crotalaria spectabilis seeds. Thorax 1967;22:176-179.
21. Kolettis T, Vlahos AP, Louka M, Hatzistergos KE, Baltogiannis GG, Agelaki MM, Mitsi A, Malamou-Mitsi V. Characterisation of a rat model of pulmonary arterial hypertension. Hell J Cardiol 2007;48:206-210.
22. Chesney CF, Allen JR. Monocrotaline induced pulmonary vascular lesions in non-human primates. Cardiovasc Res 1973;7:508-518.
23. Chesney CF, Allen JR. Endocardial fibrosis associated with monocrotaline-induced pulmonary hypertension in nonhuman primates (Macaca arctoides). Am J Vet Res 1973;34:1577-1581.
24. Gomez-Arroyo JG, Farkas L, Alhussaini AA, Farkas D, Kraskauskas D, Voelkel NF, Bogaard HJ. The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung Cell Mol Physiol 2012;302:L363-L369.
25. Shah M, Patel K, Sehgal PB. Monocrotaline pyrrole-induced endothelial cell megalocytosis involves Golgi blockade mechanism. Am J Physiol Cell Physiol 2005;288:C850-C862.
26. Stenmark KR, Meyrick B, Galiè N, Mooi WJ, McMurtry IF. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol 2009;297:L1013-L1032.
27. Ryan J, Bloch K, Archer SL. Rodent models of pulmonary hypertension: harmonisation with the World Health Organisation’s categorisation of human PH. Int J Clin Pract Suppl 2011:15-34.
28. Morrell NW, Yang X, Upton PD, Jourdan KB, Morgan N, Sheares KK, Trembath RC. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-b1 and bone morphogenetic proteins. Circulation 2001;104:790-795.
29. Atkinson C, Stewart S, Upton PD, Machado R, Thomson JR, Trembath RC, Morrell NW. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 2002;105:1672-1678.
30. Talati M, West J, Blackwell TR, Loyd JE, Meyrick B. BMPR2 mutation alters the lung macrophage endothelin-1 cascade in a mouse model and patients with heritable pulmonary artery hypertension. Am J Physiol Lung Cell Mol Physiol 2010;299:L363-L373.
31. Humbert M, Deng Z, Simonneau G, Barst RJ, Sitbon O, Wolf M, Cuervo N, et al. BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur Respir J 2002;20:518-523.
32. Zakrzewicz A, Kouri FM, Nejman B, Kwapiszewska G, Hecker M, Sandu R, Dony E, et al. The transforming growth factor-β/Smad2,3 signalling axis is impaired in experimental pulmonary hypertension. Eur Respir J 2007;29: 1094-1104.
33. Zaiman AL, Podowski M, Medicherla S, Gordy K, Xu F, Zhen L, Shimoda LA, et al. Role of the TGFβ/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension. Am J Respir Crit Care Med 2008;177:896-905.
34. Ramos MF, Lame´ MW, Segalland HJ, Wilson DW. Smad signaling in the rat model of monocrotaline pulmonary hypertension. Toxicol Pathol 2008;36(2):311-320.
35. Savai R, Pullamsetti SS, Kolbe J, Bieniek E, Voswinckel R, Fink L, Scheed A, et al. Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2012;186 (9):897-908.
36. Dahal BK, Kosanovic D, Kaulen C, Cornitescu T, Savai R, Hoffmann J, Reiss I, et al. Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats. Respir Res 2011;12:60.
37. Henriques-Coelho T, Oliveira SM, Moura RS, Roncon-Albuquerque R, Neves AL, Santos M, Nogueira-Silva C, et al. Thymulin inhibits monocrotaline-induced pulmonary hypertension modulating interleukin-6 expression and suppressing p38 pathway. Endocrinology 2008;149(9):4367-4373.
38. Dorfmüller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J 2003;22:358-363.
39. Price LC, Wort SJ, Perros F, Dorfmüller P, Huertas A, Montani D, Cohen-Kaminsky S, Humbert M. Inflammation in pulmonary arterial hypertension. Chest 2012;141:210-221.
40. Thienemann F, Henz BM, Babina M. Regulation of mast cell characteristics by cytokines: divergent effects of interleukin-4 on immature mast cell lines versus mature human skin mast cells. Arch Dermatol Res 2004;296:134-138.
41. Sueblinvong V, Weiss DJ. Stem cells and cell therapy approaches in lung biology and diseases. Transl Res 2010; 156:188-205.
42. Springer J, Lainscak M, Salobire B, Lang IM. Treatment of pulmonary hypertension: bench to bedside. Respir Med 2011;105(suppl. 1):S7-S11.
43. Reynolds AM, Holmes MD, Danilov SM, Reynolds PN. Targeted gene delivery of BMPR2 attenuates pulmonary hypertension. Eur Respir J 2012;39:329-343.
44. Bull TM, Coldren CD, Geraci, MW, Voelkel NF. Gene expression profiling in pulmonary hypertension. Proc Am Thorac Soc 2007;4:117-120.
45. Geraci MW, Moore M, Gesell T, Yeager ME, Alger L, Golpon H, Gao B, Loyd JE, Tuder RM, Voelkel NF. Gene expression patterns in the lungs of patients with primary pulmonary hypertension: a gene microarray analysis. Circ Res 2001;88:555-562.
46. Buermans HP, Redout EM, Schiel AE, Musters RJP, Zuidwijk M, Eijk PP, van Hardeveld C, et al. Microarray analysis reveals pivotal divergent mRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure. Physiol Genomics 2005;21:314-323.
47. Hamidi SA, Lin RZ, Szema AM, Lyubsky S, Jiang YP, Said SI. VIP and endothelin receptor antagonist: an effective combination against experimental pulmonary arterial hypertension. Respir Res 2011;12:141.
48. Zhao YD, Campbell AIM, Robb M, Douglas NG, Stewart DJ. Protective role of angiopoietin-1 in experimental pulmonary hypertension. Circ Res 2003;92:984-991.
49. Kamezaki F, Tasaki H, Yamashita K, Tsutsui M, Koide S, Nakata S, Tanimoto A, et al. Gene transfer of extracellular superoxide dismutase ameliorates pulmonary hypertension in rats. Am J Respir Crit Care Med 2008;177:219-226.
50. Umar S, de Visser YP, Steendijk P, Schutte CI, Laghmani EH, Wagenaar GTM, Bax WH, et al. Allogenic stem cell therapy improves right ventricular function by improving lung pathology in rats with pulmonary hypertension. Am J Physiol Heart Circ Physiol 2009;297: H1606-H1616.
51. Angelini A, Castellani C, Ravara B, Franzin C, Pozzobon M, Tavano R, Libera LD, et al. Stem-cell therapy in an experimental model of pulmonary hypertension and right heart failure: role of paracrine and neurohormonal milieu in the remodeling process. J Heart Lung Transplant 2011;30: 1281-1293.
52. Baber SR, Deng W, Master RG, Bunnell BA, Taylor BK, Murthy SN, Hyman AL, Kadowitz PJ. Intratracheal mesenchymal stem cell administration attenuates monocrotaline-induced pulmonary hypertension and endothelial dysfunction. Am J Physiol Heart Circ Physiol 2007; 292: H1120-H1128.
53. Clozel M, Hess P, Rey M, Iglarz M, Binkert C, Qiu C. Bosentan, sildenafil, and their combination in the monocrotaline model of pulmonary hypertension in rats. Exp Biol Med (Maywood) 2006;231:967-973.
54. Umar S, Iorga A, Matori H, Nadadur RD, Li J, Maltese F, van der Laarse A, Eghbali M. Estrogen rescues preexisting severe pulmonary hypertension in rats. Am J Respir Crit Care Med 2011;184:715-723.
55. Pullamsetti SS, Doebele C, Fischer A, Savai F, Kojonazarov B, Dahal BK, Ghofrani HA, et al. Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension. Am J Respir Crit Care Med 2012;185: 409-419.
56. Cowan KN, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med 2000; 6:698-702.
57. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, Sydykov A, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115:2811-2821.
58. Jiang BH, Tawara S, Abe K, Takaki A, Fukumoto Y, Shimokawa H. Acute vasodilator effect of fasudil, a Rhokinase inhibitor, in monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol 2007;49:85-89.
59. Nagaoka T, Fagan KA, Gebb SA, Morris KG, Suzuki T, Shimokawa H, McMurtry IF, Oka M. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med 2005;171: 494-499.
60. Tawara S, Fukumoto Y, Shimokawa H. Effects of combined therapy with a Rho-kinase inhibitor and prostacyclin on monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol 2007;50:195-200.
61. Hill NS, Warburton RR, Pietras L, Klinger JR. Nonspecific endothelin-receptor antagonist blunts monocrotalineinduced pulmonary hypertension in rats. J Appl Physiol 1997;83:1209-1215.
62. Schermuly RT, Kreisselmeier KP, Ghofrani HA, Yilmaz H, Butrous G, Ermert L, Ermert M, et al. Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats. Am J Respir Crit Care Med 2004; 169:39-45.
63. Wang HM, Wang Y, Liu M, Bai Y, Zhang XH, Sun YX, Wang HL. Fluoxetine inhibits monocrotaline-induced pulmonary arterial remodeling involved in inhibition of RhoARho kinase and Akt signalling pathways in rats. Can J Physiol Pharmacol 2012;90 (11):1506-1515.
64. Okada K, Tanaka Y, Bernstein M, Zhang W, Patterson GA, Botney MD. Pulmonary hemodynamics modify the rat pulmonary artery response to injury: a neointimal model of pulmonary hypertension. Am J Pathol 1997;151:1019-1025.
65. Hislop A, Reid L. New findings in pulmonary arteries of rats with hypoxia-induced pulmonary hypertension. Br J Exp Pathol 1976;57:542-554.
66. Arias-Stella J, Saldana M. The terminal portion of the pulmonary arterial tree in people native to high altitudes. Circulation 1963;28:915-925.
67. Michelakis ED, McMurtry MS, Wu XC, Dyck JRB, Moudgil R, Hopkins TA, Lopaschuk GD, Puttagunta L, Waite R, Archer SL. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation 2002;105: 244-250.
68. Muramatsu M, Tyler RC, Gutkowska J, Klinger JR, Hill NS, Rodman DM, McMurtry IF. Atrial natriuretic peptide accounts for increased cGMP in hypoxia-induced hypertensive rat lungs. Am J Physiol 1997;272:L1126-L1132.
69. Chovanec M, Novotna´ J, Wilhelm J, Hampl V, Vízek M, Herget J. Hypercapnia attenuates hypoxic pulmonary hypertension by inhibiting lung radical injury. Physiol Res 2009;58(suppl. 2):S79-S85.
70. Choudhary G, Troncales F, Martin D, Harrington EO, Klinger JR. Bosentan attenuates right ventricular hypertrophy and fibrosis in normobaric hypoxia model of pulmonary hypertension. J Heart Lung Transplant 2011;30: 827-833.
71. Abud EM, Maylor J, Undem C, Punjabi A, Zaiman AL, Myers AC, Sylvester JT, Semenza GL, Shimoda LA. Digoxin inhibits development of hypoxic pulmonary hypertension in mice. Proc Natl Acad Sci USA 2012;109:1239-1244.
72. Kantores C, McNamara PJ, Teixeira L, Engelberts D, Murthy P, Kavanagh BP, Jankov RP. Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat. Am J Physiol Lung Cell Mol Physiol 2006;291:L912-L922.
73. Resta TC, Broughton BR, Jernigan NL. Reactive oxygen species and RhoA signaling in vascular smooth muscle: role in chronic hypoxia-induced pulmonary hypertension. Adv Exp Med Biol 2010;661:355-373.
74. Xia XD, Xu ZJ, Hu XG, Wu CY, Dai YR, Yang L. Impaired iNOS-sGC-cGMP signalling contributes to chronic hypoxic and hypercapnic pulmonary hypertension in rat. Cell Biochem Funct 2012;30:279-285.
75. Archer S, Michelakis E. The mechanism(s) of hypoxic pulmonary vasoconstriction: potassium channels, redox O2 sensors, and controversies. News Physiol Sci 2002;17:131-137.
76. Voelkel NF, Tuder RM. Hypoxia-induced pulmonary vascular remodeling: a model for what human disease? J Clin Invest 2000;106:733-738.
77. Voelkel NF, Gomez-Arroyo J. The harmonics of rodent pulmonary hypertension models. Int J Clin Pract Suppl 2011:1-2.
78. Campian ME, Hardziyenka M, Michel MC, Tan HL. How valid are animal models to evaluate treatments for pulmonary hypertension? Naunyn-Schmiedebergs Arch Pharmacol 2006;373:391-400.
79. Morimatsu Y, Sakashita N, Komohara Y, Ohnishi K, Masuda H, Dahan D, Takeya M Guibert C, Marthan R. Development and characterization of an animal model of severe pulmonary arterial hypertension. J Vasc Res 2012; 49:33-42.
80. Hoshikawa Y, Nana-Sinkam P, Moore MD, Sotto-Santiago S, Phang T, Keith RL, Morris KG, et al. Hypoxia induces different genes in the lungs of rats compared with mice. Physiol Genomics 2003;12(3):209-219.
81. Fagan KA, Fouty BW, Tyler RC, Morris KG, Hepler LK, Sato K, LeCras TD, et al. The pulmonary circulation of homozygous or heterozygous eNOS-null mice is hyperresponsive to mild hypoxia. J Clin Invest 1999;103:291-299.
82. Hales CA, Kradin RL, Brandstetter RD, Zhu YJ. Impairment of hypoxic pulmonary artery remodeling by heparin in mice. Am Rev Respir Dis 1983;128(4):747-751.
83. Orton EC, Reeves JT, Stenmark KR. Pulmonary vasodilation with structurally altered pulmonary vessels and pulmonary hypertension. J Appl Physiol 1988;65:2459-2467.
84. Stenmark KR, Davie N, Frid M, Gerasimovskaya E, Das M. Role of the adventitia in pulmonary vascular remodeling. Physiology 2006;21:134-145.
85. Stenmark KR, Fasules J, Hyde DM, Voelkel NF, Henson J, Tucker A, Wilson H, Reeves JT. Severe pulmonary hypertension and arterial adventitial changes in newborn calves at 4,300 m. Appl Physiol 1987;62:821-830.
86. Das M, Dempsey EC, Bouchey D, Reyland ME, Stenmark KR. Chronic hypoxia induces exaggerated growth responses in pulmonary artery adventitial fibroblasts: potential contribution of specific protein kinase c isozymes. Am J Respir Cell Mol Biol 2000;22(1):15-25.
87. Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Reeves JT, Roedersheimer MT, van Rooijen N, Stenmark KR. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol 2006;168 (2):659-669.
88. Will DH, Alexander AF, Reeves JT, Grover RF. High altitude-induced pulmonary hypertension in normal cattle. Circ Res 1962;10:172-177.
89. Walker BR, Berend N, Voelkel NF. Comparison of muscular pulmonary arteries in low and high altitude hamsters and hypoxic rats. Respir Physiol 1984;56:45-50.
90. Yu AY, Shimoda LA, Iyer NV, Huso DL, Sun X, McWilliams R, Beaty T, et al. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α. J Clin Invest 1999;103(5):691-696.
91. Shimoda LA, Fallon M, Pisarcik S, Wang J, Semenza GL. HIF-1 regulates hypoxic induction of NHE-1 expression and alkalinisation of intracellular pH in pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 2006;291: L941-L949.
92. Stroka DM, Burkhardt T, Desbaillets I, Wenger RH, Neil DA, Bauer C, Gassmann M, Candinas D. HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia. FASEB J 2001;15 (13):2445-2453.
93. Brusselmans K, Compernolle V, Tjwa M, Wiesener MS, Maxwell PH, Collen D, Carmeliet P. Heterozygous deficiency of hypoxia-inducible factor-2α protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. J Clin Invest 2003;111(10): 1519-1527.
94. Ozaki M, Kawashima S, Yamashita T, Ohashi Y, Rikitake Y, Inoue N, Hirata KI, Hayashi Y, Itoh H, Yokoyama M. Reduced hypoxic pulmonary vascular remodeling by nitric oxide from the endothelium. Hypertension 2001;37(2): 322-327.
95. Bauer EM, Zheng H, Comhair S, Erzurum S, Billiar TR, Bauer PM. Complement C3 deficiency attenuates chronic hypoxia-induced pulmonary hypertension in mice. PLoS ONE 2011;6:e28578.
96. Yang S, Banerjee S, Freitas Ad, Cui H, Xie N, Abraham E, Liu G. MiR-21 regulates chronic hypoxia-induced pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 2012;302(6):L521-L529.
97. Cahill E, Rowan SC, Sands M, Banahan M, Ryan D, Howell K, McLoughlin P. The pathophysiological basis of chronic hypoxic pulmonary hypertension in the mouse: vasoconstrictor and structural mechanisms contribute equally. Exp Physiol 2012;97(6):796-806.
98. Dahal BK, Heuchel R, Pullamsetti SS, Wilhelm J, Ghofrani HA, Weissmann N, Seeger W, Grimminger F, Schermuly RT. Hypoxic pulmonary hypertension in mice with constitutively active platelet-derived growth factor receptor-β. Pulm Circ 2011;1(2):259-268.
99. Nisbet RE, Bland JM, Kleinhenz DJ, Mitchell PO, Walp ER, Sutliff RL, Hart CM. Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model. Am J Respir Cell Mol Biol 2010;42(4):482-490.
100. Fresquet F, Pourageaud F, Leblais V, Brandes RP, Savineau J-P, Marthan R, Muller B. Role of reactive oxygen species and gp91phox in endothelial dysfunction of pulmonary arteries induced by chronic hypoxia. Br J Pharmacol 2006;148(5):714-723.
101. Howell K, Costello CM, Sands M, Dooley I, McLoughlin P. l-Arginine promotes angiogenesis in the chronically hypoxic lung: a novel mechanism ameliorating pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2009; 296(6):L1042-L1050.
102. Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res 2006;99:675-691.
103. Abe K, Toba M, Alzoubi A, Ito M, Fagan KA, Cool CD, Voelkel NF, McMurtry IF, Oka M. Formation of plexiform lesions in experimental severe pulmonary arterial hypertension. Circulation 2010;121:2747-2754.
104. Sakao S, Tatsumi K. The effects of antiangiogenic compound SU5416 in a rat model of pulmonary arterial hypertension. Respiration 2011;81:253-261.
105. Ciuclan L, Bonneau O, Hussey M, Duggan N, Holmes AM, Good R, Stringer R, et al. A novel murine model of severe pulmonary arterial hypertension. Am J Respir Crit Care Med 2011;184:1171-1182.
106. Oka M, Homma N, Taraseviciene-Stewart L, Morris KG, Kraskauskas D, Burns N, Voelkel NF, McMurtry IF. Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats. Circ Res 2007;100:923-929.
107. Casserly B, Mazer JM, Vang A, Harrington EO, Klinger JR, Rounds S, Choudhary G. C-type natriuretic peptide does not attenuate the development of pulmonary hypertension caused by hypoxia and VEGF receptor blockade. Life Sci 2011;89:460-466.
108. Taraseviciene-Stewart L, Kasahara Y, Alger L, Hirth P, Mahon GMC, Waltenberger J, Voelkel NF, Tuder RM. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J 2001;15:427-438.
109. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thébaud B, Bonnet S, Haromy A, et al. An abnormal mitochondrial-hypoxia inducible factor-1α-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension. Circulation 2006;113: 2630-2641.
110. Sato K, Webb S, Tucker A, Rabinovitch M, O’Brien RF, McMurtry IF, Stelzner TJ. Factors influencing the idiopathic development of pulmonary hypertension in the fawn hooded rat. Am Rev Respir Dis 1992;145:793-797.
111. Rehman J, Archer SL. A proposed mitochondrial-metabolic mechanism for initiation and maintenance of pulmonary arterial hypertension in fawn-hooded rats: the Warburg model of pulmonary arterial hypertension. Adv Exp Med Biol 2010;661:171-185.
112. Nagaoka T, Gebb SA, Karoor V, Homma N, Morris KG, McMurtry IF, Oka M. Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded rat. J Appl Physiol 2006;100:996-1002.
113. Hamidi SA, Dickmann KG, Mathew S, Said SI. Pulmonary hypertension in fawn-hooded rats: rapid induction with alveolar hypoxia, correlation with upregulation of endothelin receptors, and attenuation by vasoactive intestinal peptide. Proc Am Thorac Soc 2005;2:A708.
114. Brooks A, Geldenhuys A, Zuhlke L, Human P, Zilla P. Pulmonary artery banding: still a valuable option in developing countries? Eur J Cardiothorac Surg 2012;41:272-276.
115. Muller WH Jr., Dammann JF Jr. The surgical significance of pulmonary hypertension. Ann Surg 1952;136:495-509.
116. Muller WH Jr., Longmire WP Jr. Modern development of cardiovascular surgery. Med Tech (Stuttg) 1952;15:472-475 (in German).
117. Nolan SP. The origins of pulmonary artery banding. Ann Thorac Surg 1987;44:427-429.
118. Laks H, Odim JN, Sadeghi AM, Allada V. The incisional pulmonary artery band. Ann Thorac Surg 1999;67:1813-1814.
119. Dias CA, Assad RS, Caneo LF, Abduch MC, Aiello VD, Dias AR, Marcial MB, Oliveira SA. Reversible pulmonary trunk banding. II. An experimental model for rapid pulmonary ventricular hypertrophy. J Thorac Cardiovasc Surg 2002;124:999-1006.
120. Bogaard HJ, Mizuno S, Hussaini AA, Toldo S, Abbate A, Kraskauskas D, Kasper M, Natarajan R, Voelkel NF. Suppression of histone deacetylases worsens right ventricular dysfunction after pulmonary artery banding in rats. Am J Respir Crit Care Med 2011;183:1402-1410.
121. Bogaard HJ, Natarajan R, Henderson SC, Long CS, Kraskauskas D, Smithson L, Ockaili R, McCord JM, Voelkel NF. Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure. Circulation 2009;120: 1951-1960.
122. Handoko ML, de Man FS, Allaart CP, Paulus WJ, Westerhof N, Vonk-Noordegraaf A. Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart. Eur Respir Rev 2010;19:72-82.
123. Piao L, Fang YH, Cadete VJ, Wietholt C, Urboniene D, Toth PT, Marsboom G, et al. The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med (Berl) 2010;88:47-60.
124. Fang YH, Piao L, Hong Z, Toth PT, Marsboom G, Bache-Wiig P, Rehman J, Archer SL. Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle’s cycle. JMol Med (Berl) 2012;90:31-43.
125. Ventetuolo CE, Klinger JR. WHO Group 1 pulmonary arterial hypertension: current and investigative therapies. Prog Cardiovasc Dis 2012;55:89-103.
126. Kee HJ, Kook H. Roles and targets of class I and IIa histone deacetylases in cardiac hypertrophy. J Biomed Biotechnol 2011;2011:928326.
127. Crosby A, Jones FM, Southwood M, Stewart S, Schermuly R, Butrous G, Dunne DW, Morrell NW. Pulmonary vascular remodeling correlates with lung eggs and cytokines in murine schistosomiasis. Am J Respir Crit Care Med 2010;181:279-288.
128. Graham BB, Bandeira AP, Morrell NW, Butrous G, Tuder RM. Schistosomiasis-associated pulmonary hypertension: pulmonary vascular disease: the global perspective. Chest 2010;137:20S-29S.
129. Butrous G, Ghofrani HA, Grimminger F. Pulmonary vascular disease in the developing world. Circulation 2008; 118:1758-1766.
130. Gryseels B, Polman K, Clerinx J, Kestens L. Human schistosomiasis. Lancet 2006;368:1106-1118.
131. Crosby A, Jones FM, Kolosionek E, Southwood M, Purvis I, Soon E, Butrous G, Dunne DW, Morrell NW. Praziquantel reverses pulmonary hypertension and vascular remodeling in murine schistosomiasis. Am J Respir Crit Care Med 2011;184:467-473.
132. Graham BB, Mentink-Kane MM, El-Haddad H, Purnell S, Zhang L, Zaiman A, Redente EF, et al. Schistosomiasisinduced experimental pulmonary hypertension. Am J Pathol 2010;177(3):1549-1561.
133. Brock M, Samillan VJ, Trenkmann M, Schwarzwald C, Ulrich S, Gay RE, Gassmann M, et al. AntagomiR directed against miR-20a restores functional BMPR2 signalling and prevents vascular remodelling in hypoxiainduced pulmonary hypertension. Eur Heart J 2012, doi: 10.1093/eurheartj/ehs060.
134. Austin ED, Hamid R, Hemnes AR, Machado R, Thomson JR, Trembath RC, Morrell NW. BMPR2 expression is suppressed by signaling through the estrogen receptor. Biol Sex Differ 2012;3:6.
135. Beppu H, Ichinose F, Kawai N, Jones RC, Yu PB, Zapol WM, Miyazono K, Li E, Bloch KD. BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia. Am J Physiol Lung Cell Mol Physiol 2004;287: L1241-L1247.
136. Beppu H, Kawabata M, Hamamoto T, Chytil A, Minowa O, Noda T, Miyazono K. BMP type II receptor is required for gastrulation and early development of mouse embryos. Dev Biol 2000;221:249-258.
137. Yasuda T, Tada Y, Tanabe N, Tatsumi K, West J. Rhokinase inhibition alleviates pulmonary hypertension in transgenic mice expressing a dominant-negative type II bone morphogenetic protein receptor gene. Am J Physiol Lung Cell Mol Physiol 2011;301:L667-L674.
138. Firth AL, Choi IW, Park WS. Animal models of pulmonary hypertension: Rho kinase inhibition. Prog Biophys Mol Biol 2012;109:67-75.
139. Fujita H, Fukumoto Y, Saji K, Sugimura K, Demachi J, Nawata J, Shimokawa H. Acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor, in patients with pulmonary arterial hypertension. Heart Vessels 2010; 25:144-149.
140. Said SI, Hamidi SA, Dickman KG, Szema AM, Lyubsky S, Lin RZ, Jiang Y, Chen RJ, Waschek JA, Kort S. Moderate pulmonary arterial hypertension in male mice lacking the vasoactive intestinal peptide gene. Circulation 2007; 115:1260-1268.
141. Hamidi SA, Prabhakar S, Said SI. Enhancement of pulmonary vascular remodeling and inflammatory genes with VIP gene deletion. Eur Respir J 2008;31:135-139.
142. Szema AM, Hamidi SA, Koller A, Martin DW. Vasoactive intestinal peptide knockout (VIP KO) mouse model of sulfite-sensitive asthma: up-regulation of novel lung carbonyl reductase. BMC Immunol 2011;12:66.
143. Said SI, Hamidi SA. Pharmacogenomics in pulmonary arterial hypertension: toward a mechanistic, target-based approach to therapy. Pulm Circ 2011;1:383-388.
144. Leuchte HH, Baezner C, Baumgartner RA, Bevec D, Bacher G, Neurohr C, Behr J. Inhalation of vasoactive intestinal peptide in pulmonary hypertension. Eur Respir J 2008;32:1289-1294.
145. Ivy D, McMurtry IF, Yanagisawa M, Gariepy CE, Le Cras TD, Gebb SA, Morris KG, Wiseman RC, Abman SH. Endothelin B receptor deficiency potentiates ET-1 and hypoxic pulmonary vasoconstriction. Am J Physiol Lung Cell Mol Physiol 2001;280:L1040-L1048.
146. Möller S, Uddman R, Granström B, Edvinsson L. Altered ratio of endothelin ETA-and ETB receptor mRNA in bronchial biopsies from patients with asthma and chronic airway obstruction. Eur J Pharmacol 1999;365:R1-R3.
147. Milara J, Ortiz JL, Juan G, Guijarro R, Almudever P, Martorell M, Morcillo EJ, Cortijo J. Cigarette smoke exposure up-regulates endothelin receptor B in human pulmonary artery endothelial cells: molecular and functional consequences. Br J Pharmacol 2010;161:1599-1615.
148. Weng M, Raher MJ, Leyton P, Combs TP, Scherer PE, Bloch KD, Medoff BD. Adiponectin decreases pulmonary arterial remodeling in murine models of pulmonary hypertension. Am J Respir Cell Mol Biol 2011;45:340-347.
149. Hansmann G, Wagner RA, Schellong S, de Jesus Perez VA, Urashima T, Wang L, Sheikh AY, Suen RS, Stewart DJ, Rabinovitch M. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-γ activation. Circulation 2007; 115:1275-1284.
150. Summer R, Walsh K, Medoff BD. Obesity and pulmonary arterial hypertension: is adiponectin the molecular link between these conditions? Pulm Circ 2011;1:440-447.
151. Greenow K, Pearce NJ, Ramji DP. The key role of apolipoprotein E in atherosclerosis. J Mol Med (Berl) 2005; 83:329-342.
152. Hansmann G, Rabinovitch M. The protective role of adiponectin in pulmonary vascular disease. Am J Physiol Lung Cell Mol Physiol 2010;298:L1-L2.
153. Dempsey EC, Wick MJ, Karoor V, Barr EJ, Tallman DW, Wehling CA, Walchak SJ, et al. Neprilysin null mice develop exaggerated pulmonary vascular remodeling in response to chronic hypoxia. Am J Pathol 2009;174:782-796.
154. Wick MJ, Buesing EJ, Wehling CA, Loomis ZL, Cool CD, Zamora MR, Miller YE, et al. Decreased neprilysin and pulmonary vascular remodeling in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2011;183: 330-340
155. Carpenter TC, Stenmark KR. Hypoxia decreases lung neprilysin expression and increases pulmonary vascular leak. Am J Physiol Lung Cell Mol Physiol 2001;281:L941-L948.
156. Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res 2009;104:236-244.
157. Furuya Y, Satoh T, Kuwana M. Interleukin-6 as a potential therapeutic target for pulmonary arterial hypertension. Int J Rheumatol 2010;2010:720305.
158. Savale L, Tu L, Rideau D, Izziki M, Maitre B, Adnot S, Eddahibi S. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res 2009;10:6.
159. Arita Y, Sakata Y, Sudo T, Maeda T, Matsuoka K, Tamai K, Higuchi K, et al. The efficacy of tocilizumab in a patient with pulmonary arterial hypertension associated with Castleman’s disease. Heart Vessels 2010;25:444-447.
160. Taniguchi K, Shimazaki C, Fujimoto Y, Shimura K, Uchiyama H, Matsumoto Y, Kuroda J, Horiike S, Taniwaki M. Tocilizumab is effective for pulmonary hypertension associated with multicentric Castleman’s disease. Int J Hematol 2009;90:99-102.
161. Davies RJ, Holmes AM, Deighton J, Long L, Yang X, Barker L, Walker C, Budd DC, Upton PD, Morrell NW. BMP type II receptor deficiency confers resistance to growth inhibition by TGF-β in pulmonary artery smooth muscle cells: role of proinflammatory cytokines. Am J Physiol Lung Cell Mol Physiol 2012;302:L604-L615.
162. Chu D, Sullivan CC, Du L, Cho AJ, Kido M, Wolf PL, Weitzman MD, Jamieson SW, Thistlethwaite PA. A new animal model for pulmonary hypertension based on the overexpression of a single gene, angiopoietin-1. Ann Thorac Surg 2004;77:449-457.
163. van Meurs M, Kümpers P, Ligtenberg JJ, Meertens JH, Molema G, Zijlstra JG. Bench-to-bedside review: angiopoietin signaling in critical illness—a future target? Crit Care 2009;13:207.
164. Du L, Sullivan CC, Chu D, Cho AJ, Kido M, Wolf PL, Yuan JX, Deutsch R, Jamieson SW, Thistlethwaite PA. Signaling molecules in nonfamilial pulmonary hypertension. N Engl J Med 2003;348:500-509.
165. Thistlethwaite PA, Lee SH, Du LL, Wolf PL, Sullivan C, Pradhan S, Deutsch R, Jamieson SW. Human angiopoietin gene expression is a marker for severity of pulmonary hypertension in patients undergoing pulmonary thromboendarterectomy. J Thorac Cardiovasc Surg 2001; 122:65-73.
166. Karapınar H, Esen O, Emiroğlu Y, Akçakoyun M, Pala S, Kargın R, İzgi A, Kirma C, Esen AM. Serum levels of angiopoietin-1 in patients with pulmonary hypertension due to mitral stenosis. Heart Vessels 2011;26:536-541.
167. Kümpers P, Nickel N, Lukasz A, Golpon H, Westerkamp V, Olsson KM, Jonigk D, et al. Circulating angiopoietins in idiopathic pulmonary arterial hypertension. Eur Heart J 2010;31:2291-2300.
168. Ferreira AJ, Shenoy V, Yamazato Y, Sriramula S, Francis J, Yuan L, Castellano RK, et al. Evidence for angiotensinconverting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension. Am J Respir Crit Care Med 2009;179:1048-1054.
169. MacLean MR, Deuchar GA, Hicks MN, Morecroft I, Shen S, Sheward J, Colston J, et al. Overexpression of the 5-hydroxytryptamine transporter gene: effect on pulmonary hemodynamics and hypoxia-induced pulmonary hypertension. Circulation 2004;109:2150-2155.
170. Wilkins MR. Pulmonary hypertension: the science behind the disease spectrum. Eur Respir Rev 2012;21:19-26.
171. Roberts KE, Fallon MB, Krowka MJ, Benza RL, Knowles JA, Badesch DB, Brown RS, et al. Serotonin transporter polymorphisms in patients with portopulmonary hypertension. Chest 2009;135:1470-1475.
172. Baliga RS, MacAllister RJ, Hobbs AJ. New perspectives for the treatment of pulmonary hypertension. Br J Pharmacol 2011;163:125-140.
173. Keegan A, Morecroft I, Smillie D, Hicks MN, MacLean MR. Contribution of the 5-HT1B receptor to hypoxiainduced pulmonary hypertension: converging evidence using 5-HT1B-receptor knockout mice and the 5-HT1B/1Dreceptor antagonist GR 127935. Circ Res 2001;89:1231-1239.
174. Zhu SP, Mao ZF, Huang J, Wang JY. Continuous fluoxetine administration prevents recurrence of pulmonary arterial hypertension and prolongs survival in rats. Clin Exp Pharmacol Physiol 2009;36:e1-e5.
175. Dumitrascu R, Kulcke C, Konigshoff M, Kouri F, Yang X, Morrell N, Ghofrani HA, et al. Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats. Eur Respir J 2011;37:1104-1118.
176. Ren W, Watts SW, Fanburg BL. Serotonin transporter interacts with the PDGFβ receptor in PDGF-BB-induced signaling and mitogenesis in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2011; 300:L486-L497.
177. Morecroft I, Loughlin L, Nilsen M, Colston J, Dempsie Y, Sheward J, Harmar A, MacLean MR. Functional interactions between 5-hydroxytryptamine receptors and the serotonin transporter in pulmonary arteries. J Pharmacol Exp Ther 2005;313:539-548.
178. Morecroft I, Pang L, Baranowska M, Nilsen M, Loughlin L, Dempsie Y, Millet C, MacLean MR. In vivo effects of a combined 5-HT1B receptor/SERT antagonist in experimental pulmonary hypertension. Cardiovasc Res 2010;85: 593-603.
179. Dempsie Y, MacLean MR. Pulmonary hypertension: therapeutic targets within the serotonin system. Br J Pharmacol 2008;155:455-462.
180. Ambartsumian N, Klingelhöfer J, Grigorian M, Karlstrøm O, Sidenius N, Georgiev G, Lukanidin E. Tissue-specific post-transcriptional down-regulation of expression of the S100A4(mts1) gene in transgenic animals. Invasion Metastasis 1998-1999;18:96-104.
181. Ambartsumian N, Grigorian M, Lukanidin E. Genetically modified mouse models to study the role of metastasispromoting S100A4(mts1) protein in metastatic mammary cancer. J Dairy Res 2005;72(S1):27-33.
182. Greenway S, van Suylen RJ, Du Marchie Sarvaas G, Kwan E, Ambartsumian N, Lukanidin E, Rabinovitch M. S100A4/ Mts1 produces murine pulmonary artery changes resembling plexogenic arteriopathy and is increased in human plexogenic arteriopathy. Am J Pathol 2004;164:253-262.
183. Dempsie Y, Nilsen M, White K, Mair KM, Loughlin L, Ambartsumian N, Rabinovitch M, MacLean MR. Development of pulmonary arterial hypertension in mice overexpressing S100A4/Mts1 is specific to females. Respir Res 2011;12:159.
184. Spiekerkoetter E, Lawrie A, Merklinger S, Ambartsumian N, Lukanidin E, Schmidt AM, Rabinovitch M. Mts1/ S100A4 stimulates human pulmonary artery smooth muscle cell migration through multiple signaling pathways. Chest 2005;128:577S.
185. Merklinger SL, Wagner RA, Spiekerkoetter E, Hinek A, Knutsen RH, Kabir MG, Desai K, et al. Increased fibulin-5 and elastin in S100A4/Mts1 mice with pulmonary hypertension. Circ Res 2005;97:596-604.
186. Santibañez JF, Quintanilla M, Bernabeu C. TGF-β/TGF-β receptor system and its role in physiological and pathological conditions. Clin Sci (Lond) 2011;121:233-251.