Idiopathic and Familial Pulmonary Arterial Hypertension

  • Jean M. Elwing
  • Gail H. Deutsch
  • William C. Nichols
  • Timothy D. Le Cras
Part of the Respiratory Medicine book series (RM)


Pulmonary arterial hypertension (PAH) is a progressive, fatal disease that is defined hemodynamically. The average life expectancy after diagnosis is short, with death usually due to progressive right ventricular hypertrophy and right heart failure. PAH results from vasoconstriction and structural alterations to the pulmonary vasculature. PAH can be secondary to other disorders, including underlying lung disease or it can be idiopathic without a known predisposing condition. Primary or idiopathic PAH is rare and includes individuals with a family history of disease. This chapter will focus on idiopathic and familial PAH. The discovery and history of the disease, incidence, development of the clinical classification, epidemiology, prognostic factors, and clinical assessment are reviewed. The pathology of vascular remodeling is described, including the potential sequence of events, cell types, and processes involved. The genetics of the disease together with the identification of frequent mutations in the BMPR2 gene in familial and idiopathic patients is presented. Stresses or pathways that may play a role in triggering PAH in patients with BMPR2 mutations is reviewed because of the low penetrance of symptomatic disease in families with BMPR2 mutations. Potential stimuli and pathways that can trigger the disease have been identified from clinical studies of PAH patients and from experimental models of PAH. Current therapies for PAH including general management, pharmacologic, and surgical are reviewed. Future directions in diagnosis, management, pharmacotherapies, genetic studies, pathobiology, and potential cell-based therapies are also discussed.


pulmonary arterial hypertension (PAH) familial PAH idiopathic PAH vascular remodeling BMPR-II BMPR2 



This work was supported by NIH awards HL72894 (TDLC), HL061997 (WCN), HL072058 (WCN), and an American Heart Association Established Investigator Award 0740069 N (TDLC).


  1. 1.
    Klob J. Wien Wochenbl 1865;31:45.Google Scholar
  2. 2.
    Romberg Ev. Uber Sklerose der Lungern Arterie. Dtsch Arch Klim Med 1891;48:197–206.Google Scholar
  3. 3.
    Arrilaga FC. Sclérose de l’artère pulmonaire secondaire (cardiaques noirs). Bull Mém Soc Méd Hôp Paris 1924;48:292–303.Google Scholar
  4. 4.
    Arrillaga FC. Sclérose de l’artère pulmonaire secondaire à certains états pulmonaires chroniques (cardiaques noirs). Arch Mal Coeur 1913;6:518–29.Google Scholar
  5. 5.
    Brenner O. Pathology of the vessels of the pulmonary circulation. Arch Intern Med 1935; 56:211–37, 457–97, 724–52, 976–1014, 190–241.Google Scholar
  6. 6.
    Meyer JA. Werner Forssmann and catheterization of the heart, 1929. Ann Thorac Surg 1990;49:497–9.PubMedGoogle Scholar
  7. 7.
    Forssmann W. Die Sondierung des rechten Herzens. Klin Wochnschr 1929;8:2085–7.Google Scholar
  8. 8.
    Cournand A, Riley RL, Breed ES, et al. Measurement of cardiac output in man using the technique of catheterization of the right auricle or ventricle. J Clin Invest 1945;24:106–16.PubMedGoogle Scholar
  9. 9.
    Richards DW. The contributions of right heart catheterization to physiology and medicine, with some observations on the physiopathology of pulmonary heart disease. Am Heart J 1957;54:161–71.PubMedGoogle Scholar
  10. 10.
    Richards DW. Right heart catheterization; its contributions to physiology and medicine. Science (New York, NY) 1957;125:1181–5.Google Scholar
  11. 11.
    Cournand AF, Forssmann W, Richards DW. Nobel Lectures. Amsterdam: Elsevier Publishing Company, 1964.Google Scholar
  12. 12.
    Dresdale DT, Michtom RJ, Schultz M. Recent studies in primary pulmonary hypertension, including pharmacodynamic observations on pulmonary vascular resistance. Bull N Y Acad Med 1954;30:195–207.PubMedGoogle Scholar
  13. 13.
    Fritts HW, Jr., Harris P, Clauss RH, Odell JE, Cournand A. The effect of acetylcholine on the human pulmonary circulation under normal and hypoxic conditions. J Clin Invest 1958;37:99–110.PubMedGoogle Scholar
  14. 14.
    Harris P. Influence of acetylcholine on the pulmonary arterial pressure. Br Heart J 1957;19:272–8.PubMedGoogle Scholar
  15. 15.
    Wood P, Besterman EM, Towers MK, McIlroy MB. The effect of acetylcholine on pulmonary vascular resistance and left atrial pressure in mitral stenosis. Br Heart J 1957;19:279–86.PubMedGoogle Scholar
  16. 16.
    Gurtner H. Aminorex Pulmonary Hypertension. Philadelphia, PA: University of Pennsylvania Press, 1990.Google Scholar
  17. 17.
    Hatano S, Strasser, R. Primary Pulmonary Hypertension. Geneva: World Health Organization, 1975.Google Scholar
  18. 18.
    Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:5S–12S.PubMedGoogle Scholar
  19. 19.
    Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987;107:216–23.PubMedGoogle Scholar
  20. 20.
    Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000;132:425–34.PubMedGoogle Scholar
  21. 21.
    Fishman AP. Primary pulmonary arterial hypertension: A look back. J Am Coll Cardiol 2004;43:2S–4S.PubMedGoogle Scholar
  22. 22.
    The International Primary Pulmonary Hypertension Study (IPPHS). Chest 1994;105:37S–41S.Google Scholar
  23. 23.
    Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International primary pulmonary hypertension study group. N Engl J Med 1996;335:609–16.PubMedGoogle Scholar
  24. 24.
    Newman JH, Trembath RC, Morse JA, et al. Genetic basis of pulmonary arterial hypertension: Current understanding and future directions. J Am College Cardiol 2004;43:33S–9S.Google Scholar
  25. 25.
    Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The international PPH consortium. Nat Genet 2000;26:81–4.PubMedGoogle Scholar
  26. 26.
    Dolara A, Camerini F, Menotti A, Thiene G. Primary pulmonary hypertension: An Italian multicenter study. A retrospective epidemiological survey in the period 1975–1985. Giornale Ital Cardiol 1988;18:115–20.Google Scholar
  27. 27.
    Stricker H, Domenighetti G, Popov W, et al. Severe pulmonary hypertension: Data from the Swiss registry. Swiss Med Wkly 2001;131:346–50.PubMedGoogle Scholar
  28. 28.
    Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: Results from a national registry. Am J Respir Crit Care Med 2006;173:1023–30.PubMedGoogle Scholar
  29. 29.
    Thenappan T, Shah SJ, Rich S, Gomberg-Maitland M. A United States-based registry for pulmonary arterial hypertension: 1982–2006. Eur Respir J 2007.Google Scholar
  30. 30.
    Macchia A, Marchioli R, Marfisi R, et al. A meta-analysis of trials of pulmonary hypertension: A clinical condition looking for drugs and research methodology. Am Heart J 2007;153:1037–47.PubMedGoogle Scholar
  31. 31.
    Okada O, Tanabe N, Yasuda J, et al. Prediction of life expectancy in patients with primary pulmonary hypertension. A retrospective nationwide survey from 1980–1990. Intern Med (Tokyo, Japan) 1999;38:12–6.Google Scholar
  32. 32.
    D‘Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343–9.PubMedGoogle Scholar
  33. 33.
    Rich S, Levy PS. Characteristics of surviving and nonsurviving patients with primary pulmonary hypertension. Am J Med 1984;76:573–8.PubMedGoogle Scholar
  34. 34.
    Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary arterial hypertension: Updated ACCP evidence-based clinical practice guidelines. Chest 2007;131:1917–28.PubMedGoogle Scholar
  35. 35.
    McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:14S–34S.PubMedGoogle Scholar
  36. 36.
    Rubin LJ. Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:7S–10S.PubMedGoogle Scholar
  37. 37.
    Bates B. A Guide to Physical Examination and History Taking. Philadephia: J.B. Lippincott, 5th Ed. 1991.Google Scholar
  38. 38.
    Rios JC, Massumi RA, Breesmen WT, Sarin RK. Auscultatory features of acute tricuspid regurgitation. Am J Cardiol 1969;23:4–11.PubMedGoogle Scholar
  39. 39.
    Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:40S–7S.PubMedGoogle Scholar
  40. 40.
    Chan KL, Currie PJ, Seward JB, Hagler DJ, Mair DD, Tajik AJ. Comparison of three Doppler ultrasound methods in the prediction of pulmonary artery pressure. J Am Coll Cardiol 1987;9:549–54.PubMedGoogle Scholar
  41. 41.
    Ommen SR, Nishimura RA, Hurrell DG, Klarich KW. Assessment of right atrial pressure with 2-dimensional and Doppler echocardiography: A simultaneous catheterization and echocardiographic study. Mayo Clin Proc 2000;75:24–9.PubMedGoogle Scholar
  42. 42.
    Fiegenbaum H. Echocardiography. 5th Ed. Baltimore: Williams and Wilkins, 1993.Google Scholar
  43. 43.
    Borgeson DD, Seward JB, Miller FA, Jr., Oh JK, Tajik AJ. Frequency of Doppler measurable pulmonary artery pressures. J Am Soc Echocardiogr 1996;9:832–7.PubMedGoogle Scholar
  44. 44.
    Denton CP, Cailes JB, Phillips GD, Wells AU, Black CM, Bois RM. Comparison of Doppler echocardiography and right heart catheterization to assess pulmonary hypertension in systemic sclerosis. Br J Rheumatol 1997;36:239–43.PubMedGoogle Scholar
  45. 45.
    Currie PJ, Seward JB, Chan KL, et al. Continuous wave Doppler determination of right ventricular pressure: A simultaneous Doppler-catheterization study in 127 patients. J Am Coll Cardiol 1985;6:750–6.PubMedGoogle Scholar
  46. 46.
    McQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects. Circulation 2001;104:2797–802.PubMedGoogle Scholar
  47. 47.
    Rubin LJ. Pulmonary arterial hypertension. Proc Am Thorac Soc 2006;3:111–5.PubMedGoogle Scholar
  48. 48.
    Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001;345:1465–72.PubMedGoogle Scholar
  49. 49.
    Lisbona R, Kreisman H, Novales-Diaz J, Derbekyan V. Perfusion lung scanning: Differentiation of primary from thromboembolic pulmonary hypertension. AJR Am J Roentgenol 1985;144:27–30.PubMedGoogle Scholar
  50. 50.
    Fishman AJ, Moser KM, Fedullo PF. Perfusion lung scans vs pulmonary angiography in evaluation of suspected primary pulmonary hypertension. Chest 1983;84:679–83.PubMedGoogle Scholar
  51. 51.
    Auger WR, Fedullo PF, Moser KM, Buchbinder M, Peterson KL. Chronic major-vessel thromboembolic pulmonary artery obstruction: Appearance at angiography. Radiology 1992;182:393–8.PubMedGoogle Scholar
  52. 52.
    Tan RT, Kuzo R, Goodman LR, Siegel R, Haasler GB, Presberg KW. Utility of CT scan evaluation for predicting pulmonary hypertension in patients with parenchymal lung disease. Medical College of Wisconsin Lung Transplant Group. Chest 1998;113: 1250–6.PubMedGoogle Scholar
  53. 53.
    Edwards PD, Bull RK, Coulden R. CT measurement of main pulmonary artery diameter. Br J Radiol 1998;71:1018–20.PubMedGoogle Scholar
  54. 54.
    Sitbon O, Brenot F, Denjean A, et al. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension. A dose-response study and comparison with prostacyclin. Am J Respir Crit Care Med 1995;151:384–9.PubMedGoogle Scholar
  55. 55.
    Sitbon O, Humbert M, Jagot JL, et al. Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J 1998;12:265–70.PubMedGoogle Scholar
  56. 56.
    Schrader BJ, Inbar S, Kaufmann L, Vestal RE, Rich S. Comparison of the effects of adenosine and nifedipine in pulmonary hypertension. J Am Coll Cardiol 1992;19:1060–4.PubMedGoogle Scholar
  57. 57.
    Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;111:3105–11.PubMedGoogle Scholar
  58. 58.
    Wagenvoort CA. The pathology of primary pulmonary hypertension. J Pathol 1970;101:Pi.Google Scholar
  59. 59.
    Burke AP, Farb A, Virmani R. The pathology of primary pulmonary hypertension. Mod Pathol 1991;4:269–82.PubMedGoogle Scholar
  60. 60.
    Chazova I, Loyd JE, Zhdanov VS, Newman JH, Belenkov Y, Meyrick B. Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension. Am J Pathol 1995;146:389–97.PubMedGoogle Scholar
  61. 61.
    Jamison BM, Michel RP. Different distribution of plexiform lesions in primary and secondary pulmonary hypertension. Hum Pathol 1995;26:987–93.PubMedGoogle Scholar
  62. 62.
    Bjornsson J, Edwards WD. Primary pulmonary hypertension: A histopathologic study of 80 cases. Mayo Clin Proc 1985;60:16–25.PubMedGoogle Scholar
  63. 63.
    Pietra GG, Edwards WD, Kay JM, et al. Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry. Circulation 1989;80:1198–206.PubMedGoogle Scholar
  64. 64.
    Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 1994;144:275–85.PubMedGoogle Scholar
  65. 65.
    Cool CD, Stewart JS, Werahera P, et al. Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers. Evidence for a dynamic and heterogeneous process of pulmonary endothelial cell growth. Am J Pathol 1999;155:411–9.PubMedGoogle Scholar
  66. 66.
    Tuder RM, Cool CD, Yeager M, Taraseviciene-Stewart L, Bull TM, Voelkel NF. The pathobiology of pulmonary hypertension. Endothelium. Clin Chest Med 2001;22:405–18.PubMedGoogle Scholar
  67. 67.
    Lee SD, Shroyer KR, Markham NE, Cool CD, Voelkel NF, Tuder RM. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 1998;101:927–34.PubMedGoogle Scholar
  68. 68.
    Yeager ME, Halley GR, Golpon HA, Voelkel NF, Tuder RM. Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ Res 2001;88:E2–11.PubMedGoogle Scholar
  69. 69.
    Ameshima S, Golpon H, Cool CD, et al. Peroxisome proliferator-activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ Res 2003;92:1162–9.PubMedGoogle Scholar
  70. 70.
    Cool CD, Rai PR, Yeager ME, et al. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med 2003;349:1113–22.PubMedGoogle Scholar
  71. 71.
    Taraseviciene-Stewart L, Kasahara Y, Alger L, et al. 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;15:427–38.PubMedGoogle Scholar
  72. 72.
    Voelkel NF, Cool C, Taraceviene-Stewart L, et al. Janus face of vascular endothelial growth factor: The obligatory survival factor for lung vascular endothelium controls precapillary artery remodeling in severe pulmonary hypertension. Crit Care Med 2002;30: S251–6.PubMedGoogle Scholar
  73. 73.
    Orte C, Polak JM, Haworth SG, Yacoub MH, Morrell NW. Expression of pulmonary vascular angiotensin-converting enzyme in primary and secondary plexiform pulmonary hypertension. J Pathol 2000;192:379–84.PubMedGoogle Scholar
  74. 74.
    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.PubMedGoogle Scholar
  75. 75.
    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.PubMedGoogle Scholar
  76. 76.
    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.PubMedGoogle Scholar
  77. 77.
    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.PubMedGoogle Scholar
  78. 78.
    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.PubMedGoogle Scholar
  79. 79.
    Clarke RC, Coombs CF; Hadfield G, Todd AT. On certain abnormalities, congenital and acquired, of the pulmonary artery. Q J Med 1927;21:51.Google Scholar
  80. 80.
    Loyd JE, Primm RK, Newman JH. Familial primary pulmonary hypertension: Clinical patterns. Am Rev Respir Dis 1984;129:194–7.PubMedGoogle Scholar
  81. 81.
    Austin ED, Loyd JE. Genetics and mediators in pulmonary arterial hypertension. Clin Chest Med 2007;28:43–57, vii–viii.PubMedGoogle Scholar
  82. 82.
    Loyd JE, Butler MG, Foroud TM, Conneally PM, Phillips JA, 3rd, Newman JH. Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am J Respir Crit Care Med 1995;152:93–7.PubMedGoogle Scholar
  83. 83.
    Willems PJ. Dynamic mutations hit double figures. Nat Genet 1994;8:213–5.PubMedGoogle Scholar
  84. 84.
    Nichols WC, Koller DL, Slovis B, et al. Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31–32. Nat Genet 1997;15:277–80.PubMedGoogle Scholar
  85. 85.
    Morse JH, Jones AC, Barst RJ, Hodge SE, Wilhelmsen KC, Nygaard TG. Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31–q32. Circulation 1997;95:2603–6.PubMedGoogle Scholar
  86. 86.
    Machado RD, Pauciulo MW, Fretwell N, et al. A physical and transcript map based upon refinement of the critical interval for PPH1, a gene for familial primary pulmonary hypertension. The International PPH Consortium. Genomics 2000;68:220–8.PubMedGoogle Scholar
  87. 87.
    Kawabata M, Chytil A, Moses HL. Cloning of a novel type II serine/threonine kinase receptor through interaction with the type I transforming growth factor-beta receptor. J Biol Chem 1995;270:5625–30.PubMedGoogle Scholar
  88. 88.
    Botney MD, Bahadori L, Gold LI. Vascular remodeling in primary pulmonary hypertension. Potential role for transforming growth factor-beta. Am J Pathol 1994;144: 286–95.PubMedGoogle Scholar
  89. 89.
    Marchuk DA. Genetic abnormalities in hereditary hemorrhagic telangiectasia. Curr Opin Hematol 1998;5:332–8.PubMedGoogle Scholar
  90. 90.
    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.PubMedGoogle Scholar
  91. 91.
    Cogan JD, Pauciulo MW, Batchman AP, et al. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med 2006;174:590–8.PubMedGoogle Scholar
  92. 92.
    Aldred MA, Vijayakrishnan J, James V, et al. BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat 2006;27:212–3.PubMedGoogle Scholar
  93. 93.
    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.PubMedGoogle Scholar
  94. 94.
    Koehler R, Grunig E, Pauciulo MW, 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.PubMedGoogle Scholar
  95. 95.
    Morisaki H, Nakanishi N, Kyotani S, Takashima A, Tomoike H, Morisaki T. BMPR2 mutations found in Japanese patients with familial and sporadic primary pulmonary hypertension. Hum Mutat 2004;23:632.PubMedGoogle Scholar
  96. 96.
    Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 2000;37:741–5.PubMedGoogle Scholar
  97. 97.
    Eddahibi S, Hanoun N, Lanfumey L, et al. Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest 2000;105: 1555–62.PubMedGoogle Scholar
  98. 98.
    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.PubMedGoogle Scholar
  99. 99.
    Eddahibi S, Raffestin B, Pham I, et al. Treatment with 5-HT potentiates development of pulmonary hypertension in chronically hypoxic rats. Am J Physiol 1997;272:H1173–81.PubMedGoogle Scholar
  100. 100.
    Eddahibi S, Adnot S. The serotonin pathway in pulmonary hypertension. Arch Mal Coeur Vaiss 2006;99:621–5.PubMedGoogle Scholar
  101. 101.
    Machado RD, Koehler R, Glissmeyer E, et al. Genetic association of the serotonin transporter in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006;173:793–7.PubMedGoogle Scholar
  102. 102.
    Willers ED, Newman JH, Loyd JE, et al. Serotonin transporter polymorphisms in familial and idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2006;173:798–802.PubMedGoogle Scholar
  103. 103.
    Trembath RC, Thomson JR, Machado RD, et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2001;345:325–34.PubMedGoogle Scholar
  104. 104.
    Harrison RE, Flanagan JA, Sankelo M, et al. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet 2003;40:865–71.PubMedGoogle Scholar
  105. 105.
    Abdalla SA, Gallione CJ, Barst RJ, et al. Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia. Eur Respir J 2004;23:373–7.PubMedGoogle Scholar
  106. 106.
    McAllister KA, Grogg KM, Johnson DW, et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 1994;8:345–51.PubMedGoogle Scholar
  107. 107.
    Johnson DW, Berg JN, Baldwin MA, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996;13:189–95.PubMedGoogle Scholar
  108. 108.
    Harrison RE, Berger R, Haworth SG, et al. Transforming growth factor-beta receptor mutations and pulmonary arterial hypertension in childhood. Circulation 2005;111:435–41.PubMedGoogle Scholar
  109. 109.
    Chaouat A, Coulet F, Favre C, et al. Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. Thorax 2004;59:446–8.PubMedGoogle Scholar
  110. 110.
    Fernandez LA, Sanz-Rodriguez F, Blanco FJ, Bernabeu C, Botella LM. Hereditary hemorrhagic telangiectasia, a vascular dysplasia affecting the TGF-beta signaling pathway. Clin Med Res 2006;4:66–78.Google Scholar
  111. 111.
    Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004;109:159–65.PubMedGoogle Scholar
  112. 112.
    Riddell DR, Owen JS. Nitric oxide and platelet aggregation. Vitam Horm 1999;57:25–48.PubMedGoogle Scholar
  113. 113.
    Knowles RG, Moncada S. Nitric oxide synthases in mammals. Biochem J 1994;298 (Pt 2):249–58.PubMedGoogle Scholar
  114. 114.
    Abman SH, Chatfield BA, Hall SL, McMurtry IF. Role of endothelium-derived relaxing factor during transition of pulmonary circulation at birth. Am J Physiol 1990;259:H1921–7.PubMedGoogle Scholar
  115. 115.
    Cooper CJ, Landzberg MJ, Anderson TJ, et al. Role of nitric oxide in the local regulation of pulmonary vascular resistance in humans. Circulation 1996;93:266–71.PubMedGoogle Scholar
  116. 116.
    Sogo N, Magid KS, Shaw CA, Webb DJ, Megson IL. Inhibition of human platelet aggregation by nitric oxide donor drugs: Relative contribution of cGMP-independent mechanisms. Biochem Biophys Res Commun 2000;279:412–9.PubMedGoogle Scholar
  117. 117.
    Wang YF, Tian H, Tang CS, Jin HF, Du JB. Nitric oxide modulates hypoxic pulmonary smooth muscle cell proliferation and apoptosis by regulating carbon monoxide pathway. Acta Pharmacol Sin 2007;28:28–35.PubMedGoogle Scholar
  118. 118.
    Ignarro LJ, Buga GM, Wei LH, Bauer PM, Wu G, del Soldato P. Role of the arginine–nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation. Proc Natl Acad Sci USA 2001;98:4202–8.PubMedGoogle Scholar
  119. 119.
    Roos CM, Frank DU, Xue C, Johns RA, Rich GF. Chronic inhaled nitric oxide: Effects on pulmonary vascular endothelial function and pathology in rats. J Appl Physiol 1996;80:252–60.PubMedGoogle Scholar
  120. 120.
    Fagan KA, Fouty BW, Tyler RC, et al. The pulmonary circulation of homozygous or heterozygous eNOS-null mice is hyperresponsive to mild hypoxia. J Clin Invest 1999;103:291–9.PubMedGoogle Scholar
  121. 121.
    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.PubMedGoogle Scholar
  122. 122.
    Xue C, Johns RA. Endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333:1642–4.PubMedGoogle Scholar
  123. 123.
    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.PubMedGoogle Scholar
  124. 124.
    Kielstein JT, Bode-Boger SM, Hesse G, et al. Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 2005;25:1414–8.PubMedGoogle Scholar
  125. 125.
    Boger RH. Association of asymmetric dimethylarginine and endothelial dysfunction. Clin Chem Lab Med 2003;41:1467–72.PubMedGoogle Scholar
  126. 126.
    Tran CT, Leiper JM, Vallance P. The DDAH/ADMA/NOS pathway. Atheroscler Suppl 2003;4:33–40.PubMedGoogle Scholar
  127. 127.
    Boger RH. Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the ``L-arginine paradox’ and acts as a novel cardiovascular risk factor. J Nutr 2004;134:2842S–7S; discussion 53S.PubMedGoogle Scholar
  128. 128.
    Luscher TF. Endothelium-derived vasoactive factors and regulation of vascular tone in human blood vessels. Lung 1990;168 Suppl:27–34.PubMedGoogle Scholar
  129. 129.
    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.PubMedGoogle Scholar
  130. 130.
    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.PubMedGoogle Scholar
  131. 131.
    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.PubMedGoogle Scholar
  132. 132.
    Fike CD, Zhang Y, Kaplowitz MR. Thromboxane inhibition reduces an early stage of chronic hypoxia-induced pulmonary hypertension in piglets. J Appl Physiol 2005;99:670–6.PubMedGoogle Scholar
  133. 133.
    Fike CD, Pfister SL, Kaplowitz MR, Madden JA. Cyclooxygenase contracting factors and altered pulmonary vascular responses in chronically hypoxic newborn pigs. J Appl Physiol 2002;92:67–74.PubMedGoogle Scholar
  134. 134.
    Fike CD, Kaplowitz MR, Zhang Y, Pfister SL. Cyclooxygenase-2 and an early stage of chronic hypoxia-induced pulmonary hypertension in newborn pigs. J Appl Physiol 2005;98:1111–8; discussion 091.PubMedGoogle Scholar
  135. 135.
    Fike CD, Kaplowitz MR, Pfister SL. Arachidonic acid metabolites and an early stage of pulmonary hypertension in chronically hypoxic newborn pigs. Am J Physiol 2003;284:L316–23.Google Scholar
  136. 136.
    Kowala MC. The role of endothelin in the pathogenesis of atherosclerosis. Adv Pharmacol 1997;37:299–318.PubMedGoogle Scholar
  137. 137.
    Davenport AP, Maguire JJ. Endothelin. Handb Exp Pharmacol 2006;176:295–329.PubMedGoogle Scholar
  138. 138.
    Wort SJ, Woods M, Warner TD, Evans TW, Mitchell JA. Endogenously released endothelin-1 from human pulmonary artery smooth muscle promotes cellular proliferation: Relevance to pathogenesis of pulmonary hypertension and vascular remodeling. Am J Respir Cell Mol Biol 2001;25:104–10.PubMedGoogle Scholar
  139. 139.
    Rockey DC, Chung JJ. Endothelin antagonism in experimental hepatic fibrosis. Implications for endothelin in the pathogenesis of wound healing. J Clin Invest 1996;98:1381–8.PubMedGoogle Scholar
  140. 140.
    Sampaio AL, Rae GA, Henriques MG. Effects of endothelin ETA receptor antagonism on granulocyte and lymphocyte accumulation in LPS-induced inflammation. J Leukoc Biol 2004;76:210–6.PubMedGoogle Scholar
  141. 141.
    Hirata Y, Emori T, Eguchi S, et al. Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells. J Clin Invest 1993;91:1367–73.PubMedGoogle Scholar
  142. 142.
    Hirata Y, Hayakawa H, Suzuki E, et al. Direct measurements of endothelium-derived nitric oxide release by stimulation of endothelin receptors in rat kidney and its alteration in salt-induced hypertension. Circulation 1995;91:1229–35.PubMedGoogle Scholar
  143. 143.
    Luscher TF. Endothelin, endothelin receptors, and endothelin antagonists. Curr Opin Nephrol Hypertens 1994;3:92–8.PubMedGoogle Scholar
  144. 144.
    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.PubMedGoogle Scholar
  145. 145.
    Cacoub P, Dorent R, Nataf P, et al. Endothelin-1 in the lungs of patients with pulmonary hypertension. Cardiovasc Res 1997;33:196–200.PubMedGoogle Scholar
  146. 146.
    Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: Marker or mediator of disease? Ann Intern Med 1991;114:464–9.PubMedGoogle Scholar
  147. 147.
    DiCarlo VS, Chen SJ, Meng QC, et al. ETA-receptor antagonist prevents and reverses chronic hypoxia-induced pulmonary hypertension in rat. Am J Physiol 1995;269:L690–7.PubMedGoogle Scholar
  148. 148.
    Chen YF, Oparil S. Endothelin and pulmonary hypertension. J Cardiovasc Pharmacol 2000;35:S49–53.PubMedGoogle Scholar
  149. 149.
    Chen YF, Oparil S. Endothelial dysfunction in the pulmonary vascular bed. Am J Med Sci 2000;320:223–32.PubMedGoogle Scholar
  150. 150.
    Chen SJ, Chen YF, Opgenorth TJ, et al. The orally active nonpeptide endothelin A-receptor antagonist A-127722 prevents and reverses hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in Sprague–Dawley rats. J Cardiovasc Pharmacol 1997;29:713–25.PubMedGoogle Scholar
  151. 151.
    Chen SJ, Chen YF, Meng QC, Durand J, Dicarlo VS, Oparil S. Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats. J Appl Physiol 1995;79:2122–31.PubMedGoogle Scholar
  152. 152.
    Ambalavanan N, Philips JB, 3rd, Bulger A, Oparil S, Chen YF. Endothelin-A receptor blockade in porcine pulmonary hypertension. Pediatr Res 2002;52:913–21.PubMedGoogle Scholar
  153. 153.
    Ambalavanan N, Bulger A, Murphy-Ullrich J, Oparil S, Chen YF. Endothelin-A receptor blockade prevents and partially reverses neonatal hypoxic pulmonary vascular remodeling. Pediatr Res 2005;57:631–6.PubMedGoogle Scholar
  154. 154.
    Ivy DD, Yanagisawa M, Gariepy CE, Gebb SA, Colvin KL, McMurtry IF. Exaggerated hypoxic pulmonary hypertension in endothelin B receptor-deficient rats. Am J Physiol 2002;282:L703–12.Google Scholar
  155. 155.
    Ivy DD, Parker TA, Ziegler JW, et al. Prolonged endothelin A receptor blockade attenuates chronic pulmonary hypertension in the ovine fetus. J Clin Invest 1997;99:1179–86.PubMedGoogle Scholar
  156. 156.
    Ivy DD, Parker TA, Kinsella JP, Abman SH. Endothelin A receptor blockade decreases pulmonary vascular resistance in premature lambs with hyaline membrane disease. Pediatr Res 1998;44:175–80.PubMedGoogle Scholar
  157. 157.
    Ivy DD, Parker TA, Abman SH. Prolonged endothelin B receptor blockade causes pulmonary hypertension in the ovine fetus. Am J Physiol 2000;279:L758–65.Google Scholar
  158. 158.
    Ivy D, McMurtry IF, Yanagisawa M, et al. Endothelin B receptor deficiency potentiates ET-1 and hypoxic pulmonary vasoconstriction. Am J Physiol 2001;280:L1040–8.Google Scholar
  159. 159.
    Li H, Chen SJ, Chen YF, et al. Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia. J Appl Physiol 1994;77:1451–9.PubMedGoogle Scholar
  160. 160.
    Frasch HF, Marshall C, Marshall BE. Endothelin-1 is elevated in monocrotaline pulmonary hypertension. Am J Physiol 1999;276:L304–10.PubMedGoogle Scholar
  161. 161.
    Balasubramaniam V, Le Cras TD, Ivy DD, Grover TR, Kinsella JP, Abman SH. Role of platelet-derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus. Am J Physiol 2003;284:L826–33.Google Scholar
  162. 162.
    Le Cras TD, Markham NE, Tuder RM, Voelkel NF, Abman SH. Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structure. Am J Physiol 2002;283:L555–62.Google Scholar
  163. 163.
    Merklinger SL, Jones PL, Martinez EC, Rabinovitch M. Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 2005;112:423–31.PubMedGoogle Scholar
  164. 164.
    Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115:2811–21.PubMedGoogle Scholar
  165. 165.
    Barst RJ. PDGF signaling in pulmonary arterial hypertension. J Clin Invest 2005;115:2691–4.PubMedGoogle Scholar
  166. 166.
    Katayose D, Ohe M, Yamauchi K, et al. Increased expression of PDGF A- and B-chain genes in rat lungs with hypoxic pulmonary hypertension. Am J Physiol 1993;264: L100–6.PubMedGoogle Scholar
  167. 167.
    Kasahara Y, Tuder RM, Taraseviciene-Stewart L, et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000;106:1311–9.PubMedGoogle Scholar
  168. 168.
    Grover TR, Parker TA, Zenge JP, Markham NE, Kinsella JP, Abman SH. Intrauterine hypertension decreases lung VEGF expression and VEGF inhibition causes pulmonary hypertension in the ovine fetus. Am J Physiol 2003;284:L508–17.Google Scholar
  169. 169.
    Ingram JL, Bonner JC. EGF and PDGF receptor tyrosine kinases as therapeutic targets for chronic lung diseases. Curr Mol Med 2006;6:409–21.PubMedGoogle Scholar
  170. 170.
    Waheed S, D‘Angio CT, Wagner CL, et al. Transforming growth factor alpha (TGF(alpha)) is increased during hyperoxia and fibrosis. Exp Lung Res 2002;28:361–72.PubMedGoogle Scholar
  171. 171.
    Liu JQ, Folz RJ. Extracellular superoxide enhances 5-HT-induced murine pulmonary artery vasoconstriction. Am J Physiol 2004;287:L111–8.Google Scholar
  172. 172.
    Lee SL, Wang WW, Moore BJ, Fanburg BL. Dual effect of serotonin on growth of bovine pulmonary artery smooth muscle cells in culture. Circ Res 1991;68:1362–8.PubMedGoogle Scholar
  173. 173.
    Pitt BR, Weng W, Steve AR, Blakely RD, Reynolds I, Davies P. Serotonin increases DNA synthesis in rat proximal and distal pulmonary vascular smooth muscle cells in culture. Am J Physiol 1994;266:L178–86.PubMedGoogle Scholar
  174. 174.
    Lee SL, Wang WW, Lanzillo JJ, Fanburg BL. Serotonin produces both hyperplasia and hypertrophy of bovine pulmonary artery smooth muscle cells in culture. Am J Physiol 1994;266:L46–52.PubMedGoogle Scholar
  175. 175.
    Rickaby DA, Dawson CA, Maron MB. Pulmonary inactivation of serotonin and site of serotonin pulmonary vasoconstriction. J Appl Physiol 1980;48:606–12.PubMedGoogle Scholar
  176. 176.
    Eddahibi S, Fabre V, Boni C, et al. Induction of serotonin transporter by hypoxia in pulmonary vascular smooth muscle cells. Relationship with the mitogenic action of serotonin. Circ Res 1999;84:329–36.PubMedGoogle Scholar
  177. 177.
    Rapaport E, Rolston WA, Stern S. The role of adrenergic receptor blockade in serotonin-induced changes in the pulmonary circulation. J Physiol 1977;273:83–107.PubMedGoogle Scholar
  178. 178.
    Martin TR, Cohen ML, Drazen JM. Serotonin-induced pulmonary responses are mediated by the 5-HT2 receptor in the mouse. J Pharmacol Exp Ther 1994;268:104–9.PubMedGoogle Scholar
  179. 179.
    Song D, Wang HL, Wang S, Zhang XH. 5-Hydroxytryptamine-induced proliferation of pulmonary artery smooth muscle cells are extracellular signal-regulated kinase pathway dependent. Acta Pharmacol Sin 2005;26:563–7.PubMedGoogle Scholar
  180. 180.
    Lawrie A, Spiekerkoetter E, Martinez EC, et al. Interdependent serotonin transporter and receptor pathways regulate S100A4/Mts1, a gene associated with pulmonary vascular disease. Circ Res 2005;97:227–35.PubMedGoogle Scholar
  181. 181.
    Widgren S. Pulmonary hypertension related to aminorex intake. Histologic, ultrastructural, and morphometric studies of 37 cases in Switzerland. Curr Top Pathol 1977;64:1–64.PubMedGoogle Scholar
  182. 182.
    Rothman RB, Ayestas MA, Dersch CM, Baumann MH. Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates. Implications for primary pulmonary hypertension. Circulation 1999;100:869–75.PubMedGoogle Scholar
  183. 183.
    Gurtner HP. Aminorex and pulmonary hypertension. A review. Cor Vasa 1985;27:160–71.PubMedGoogle Scholar
  184. 184.
    Simonneau G, Fartoukh M, Sitbon O, Humbert M, Jagot JL, Herve P. Primary pulmonary hypertension associated with the use of fenfluramine derivatives. Chest 1998;114:195S–9S.PubMedGoogle Scholar
  185. 185.
    Rich S, Rubin L, Walker AM, Schneeweiss S, Abenhaim L. Anorexigens and pulmonary hypertension in the United States: Results from the surveillance of North American pulmonary hypertension. Chest 2000;117:870–4.PubMedGoogle Scholar
  186. 186.
    Herve P, Humbert M, Sitbon O, et al. Pathobiology of pulmonary hypertension. The role of platelets and thrombosis. Clin Chest Med 2001;22:451–8.PubMedGoogle Scholar
  187. 187.
    Sato K, Webb S, Tucker A, et al. Factors influencing the idiopathic development of pulmonary hypertension in the fawn hooded rat. Am Rev Respir Dis 1992;145:793–7.PubMedGoogle Scholar
  188. 188.
    Eddahibi S, Humbert M, Fadel E, et al. Hyperplasia of pulmonary artery smooth muscle cells is causally related to overexpression of the serotonin transporter in primary pulmonary hypertension. Chest 2002;121:97S–8S.PubMedGoogle Scholar
  189. 189.
    Long L, MacLean MR, Jeffery TK, et al. Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circ Res 2006;98:818–27.PubMedGoogle Scholar
  190. 190.
    Morrell NW, Yang X, Upton PD, et al. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins. Circulation 2001;104:790–5.PubMedGoogle Scholar
  191. 191.
    Yang X, Long L, Southwood M, et al. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res 2005;96:1053–63.PubMedGoogle Scholar
  192. 192.
    Dey RD, Shannon WA, Jr., Said SI. Localization of VIP-immunoreactive nerves in airways and pulmonary vessels of dogs, cat, and human subjects. Cell Tissue Res 1981;220: 231–8.PubMedGoogle Scholar
  193. 193.
    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.PubMedGoogle Scholar
  194. 194.
    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.PubMedGoogle Scholar
  195. 195.
    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.PubMedGoogle Scholar
  196. 196.
    Said SI. Mediators and modulators of pulmonary arterial hypertension. Am J Physiol 2006;291:L547–58.Google Scholar
  197. 197.
    Jones PL, Cowan KN, Rabinovitch M. Tenascin-C, proliferation and subendothelial fibronectin in progressive pulmonary vascular disease. Am J Pathol 1997;150:1349–60.PubMedGoogle Scholar
  198. 198.
    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 2006;291:L694–702.Google Scholar
  199. 199.
    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.PubMedGoogle Scholar
  200. 200.
    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.PubMedGoogle Scholar
  201. 201.
    Jones FS, Meech R, Edelman DB, Oakey RJ, Jones PL. Prx1 controls vascular smooth muscle cell proliferation and tenascin-C expression and is upregulated with Prx2 in pulmonary vascular disease. Circ Res 2001;89:131–8.PubMedGoogle Scholar
  202. 202.
    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.PubMedGoogle Scholar
  203. 203.
    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.PubMedGoogle Scholar
  204. 204.
    Zaidi SH, You XM, Ciura S, Husain M, Rabinovitch M. Overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension. Circulation 2002;105:516–21.PubMedGoogle Scholar
  205. 205.
    Greenway S, van Suylen RJ, Du Marchie Sarvaas G, et al. S100A4/Mts1 produces murine pulmonary artery changes resembling plexogenic arteriopathy and is increased in human plexogenic arteriopathy. Am J Pathol 2004;164:253–62.PubMedGoogle Scholar
  206. 206.
    Voelkel NF, Cool C, Lee SD, Wright L, Geraci MW, Tuder RM. Primary pulmonary hypertension between inflammation and cancer. Chest 1998;114:225S–30S.PubMedGoogle Scholar
  207. 207.
    Tuder RM, Voelkel NF. Pulmonary hypertension and inflammation. J Lab Clin Med 1998;132:16–24.PubMedGoogle Scholar
  208. 208.
    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.PubMedGoogle Scholar
  209. 209.
    Dorfmuller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J 2003;22:358–63.PubMedGoogle Scholar
  210. 210.
    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.PubMedGoogle Scholar
  211. 211.
    Speich R, Jenni R, Opravil M, Pfab M, Russi EW. Primary pulmonary hypertension in HIV infection. Chest 1991;100:1268–71.PubMedGoogle Scholar
  212. 212.
    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 1992;145:1196–200.PubMedGoogle Scholar
  213. 213.
    Montani D, Marcelin AG, Sitbon O, Calvez V, Simonneau G, Humbert M. Human herpes virus 8 in HIV and non-HIV infected patients with pulmonary arterial hypertension in France. Aids 2005;19:1239–40.PubMedGoogle Scholar
  214. 214.
    Friedrich EB, Bohm M. Human herpes virus-8-encoded chemokine receptor homologues: Novel mechanistic link for pulmonary arterial hypertension? J Mol Cell Cardiol 2007;42:487–8.PubMedGoogle Scholar
  215. 215.
    Speikerkoetter EF, Alvira CM, Bruneau A, et al. A herpes virus infection (y-MHV-68) induces hightened elastase activity and elastin peptides, promoting pulmonary vascular disease (PVD) in Mts1 mice. Am J Respir Crit Care Med 2007;175:A289.Google Scholar
  216. 216.
    Post JM, Hume JR, Archer SL, Weir EK. Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction. Am J Physiol 1992;262:C882–90.PubMedGoogle Scholar
  217. 217.
    Michelakis ED, Archer SL, Weir EK. Acute hypoxic pulmonary vasoconstriction: A model of oxygen sensing. Physiol Res 1995;44:361–7.PubMedGoogle Scholar
  218. 218.
    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.PubMedGoogle Scholar
  219. 219.
    Weir EK, Archer SL. The mechanism of acute hypoxic pulmonary vasoconstriction: The tale of two channels. FASEB J 1995;9:183–9.PubMedGoogle Scholar
  220. 220.
    Archer S, Rich S. Primary pulmonary hypertension: A vascular biology and translational research "Work in progress". Circulation 2000;102:2781–91.PubMedGoogle Scholar
  221. 221.
    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.PubMedGoogle Scholar
  222. 222.
    Young KA, Ivester C, West J, Carr M, Rodman DM. BMP signaling controls PASMC KV channel expression in vitro and in vivo. Am J Physiol 2006;290:L841–8.Google Scholar
  223. 223.
    Kimura K, Ito M, Amano M, et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science (New York, NY) 1996;273:245–8.PubMedGoogle Scholar
  224. 224.
    Nagaoka T, Morio Y, Casanova N, et al. Rho/Rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats. Am J Physiol 2004;287:L665–72.Google Scholar
  225. 225.
    Winaver J, Ovcharenko E, Rubinstein I, et al. Involvement of Rho kinase pathway in the mechanism of renal vasoconstriction and cardiac hypertrophy in rats with experimental heart failure. Am J Physiol Heart Circ Physiol 2006;290:H2007–14.PubMedGoogle Scholar
  226. 226.
    Wang YX, da Cunha V, Martin-McNulty B, et al. Inhibition of Rho-kinase by fasudil attenuated angiotensin II-induced cardiac hypertrophy in apolipoprotein E deficient mice. Eur J Pharmacol 2005;512:215–22.PubMedGoogle Scholar
  227. 227.
    Satoh S, Ueda Y, Koyanagi M, et al. Chronic inhibition of Rho kinase blunts the process of left ventricular hypertrophy leading to cardiac contractile dysfunction in hypertension-induced heart failure. J Mol Cell Cardiol 2003;35:59–70.PubMedGoogle Scholar
  228. 228.
    Pan M, Jing HM, Zhu JH, Liu ZH, Jiang WP, Yang XJ. Rho-kinase inhibitor may exert a role in preventing cardiac hypertrophy, independent of antihypertensive effects. Med Hypotheses 2007;68:234.PubMedGoogle Scholar
  229. 229.
    Balakumar P, Singh M. Differential role of rho-kinase in pathological and physiological cardiac hypertrophy in rats. Pharmacology 2006;78:91–7.PubMedGoogle Scholar
  230. 230.
    Inokuchi K, Ito A, Fukumoto Y, et al. Usefulness of fasudil, a Rho-kinase inhibitor, to treat intractable severe coronary spasm after coronary artery bypass surgery. J Cardiovasc Pharmacol 2004;44:275–7.PubMedGoogle Scholar
  231. 231.
    Masumoto A, Mohri M, Shimokawa H, Urakami L, Usui M, Takeshita A. Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation 2002;105:1545–7.PubMedGoogle Scholar
  232. 232.
    Fukumoto Y, Mohri M, Inokuchi K, et al. Anti-ischemic effects of fasudil, a specific Rho-kinase inhibitor, in patients with stable effort angina. J Cardiovasc Pharmacol 2007;49:117–21.PubMedGoogle Scholar
  233. 233.
    Li M, Liu Y, Dutt P, Fanburg B, Toksoz D. Inhibition of serotonin-induced mitogenesis, migration, and ERK MAPK nuclear translocation in vascular smooth muscle cells by atorvastatin. Am J Physiol 2007;293(2):L463–L471.Google Scholar
  234. 234.
    Barman SA. Vasoconstrictor effect of Endothelin-1 on hypertensive pulmonary arterial smooth muscle involves Rho kinase and protein kinase C. Am J Physiol 2007; 293(2):L472–9.Google Scholar
  235. 235.
    Chapados R, Abe K, Ihida-Stansbury K, et al. ROCK controls matrix synthesis in vascular smooth muscle cells: Coupling vasoconstriction to vascular remodeling. Circ Res 2006;99:837–44.PubMedGoogle Scholar
  236. 236.
    Nagaoka T, Fagan KA, Gebb SA, et al. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med 2005;171:494–9.PubMedGoogle Scholar
  237. 237.
    Jiang BH, Tawara S, Abe K, Takaki A, Fukumoto Y, Shimokawa H. Acute vasodilator effect of fasudil, a Rho-kinase inhibitor, in monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol 2007;49:85–9.PubMedGoogle Scholar
  238. 238.
    Abe K, Shimokawa H, Morikawa K, et al. Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res 2004;94:385–93.PubMedGoogle Scholar
  239. 239.
    Li FH, Xia W, Li AW, Zhao CF, Sun RP. Inhibition of rho kinase attenuates high flow induced pulmonary hypertension in rats. Chin Med J (Engl) 2007;120:22–9.Google Scholar
  240. 240.
    Li F, Xia W, Li A, Zhao C, Sun R. Long-term inhibition of Rho kinase with fasudil attenuates high flow induced pulmonary artery remodeling in rats. Pharmacol Res 2007;55:64–71.PubMedGoogle Scholar
  241. 241.
    Oka M, Homma N, Taraseviciene-Stewart L, et al. Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats. Circ Res 2007;100:923–9.PubMedGoogle Scholar
  242. 242.
    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.PubMedGoogle Scholar
  243. 243.
    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.PubMedGoogle Scholar
  244. 244.
    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.PubMedGoogle Scholar
  245. 245.
    Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:35S–62S.PubMedGoogle Scholar
  246. 246.
    Weiss BM, Zemp L, Seifert B, Hess OM. Outcome of pulmonary vascular disease in pregnancy: A systematic overview from 1978 through 1996. J Am Coll Cardiol 1998;31:1650–7.PubMedGoogle Scholar
  247. 247.
    Galie N, Torbicki A, Barst R, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The task force on diagnosis and treatment of pulmonary arterial hypertension of the European Society of Cardiology. Eur Heart J 2004;25:2243–78.PubMedGoogle Scholar
  248. 248.
    Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76–81.PubMedGoogle Scholar
  249. 249.
    Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: Natural history and the importance of thrombosis. Circulation 1984;70:580–7.PubMedGoogle Scholar
  250. 250.
    Landmark K, Refsum AM, Simonsen S, Storstein O. Verapamil and pulmonary hypertension. Acta Med Scand 1978;204:299–302.PubMedGoogle Scholar
  251. 251.
    Libby P, Warner SJ, Friedman GB. Interleukin 1: A mitogen for human vascular smooth muscle cells that induces the release of growth-inhibitory prostanoids. J Clin Invest 1988;81:487–98.PubMedGoogle Scholar
  252. 252.
    Owen NE. Prostacyclin Can Inhibit DNA Synthesis in Vascular Smooth Muscle Cells. New York, NY: Plenum Press, 1985.Google Scholar
  253. 253.
    Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;334:296–302.PubMedGoogle Scholar
  254. 254.
    Tapson VF, Gomberg-Maitland M, McLaughlin VV, et al. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: A prospective, multicenter, open-label, 12-week trial. Chest 2006;129:683–8.PubMedGoogle Scholar
  255. 255.
    Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: A double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165:800–4.PubMedGoogle Scholar
  256. 256.
    Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322–9.PubMedGoogle Scholar
  257. 257.
    McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006;174:1257–63.PubMedGoogle Scholar
  258. 258.
    Hoeper MM, Schwarze M, Ehlerding S, et al. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med 2000;342:1866–70.PubMedGoogle Scholar
  259. 259.
    Opitz CF, Wensel R, Winkler J, et al. Clinical efficacy and survival with first-line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension. Eur Heart J 2005;26:1895–902.PubMedGoogle Scholar
  260. 260.
    Benigni A, Remuzzi G. Endothelin antagonists. Lancet 1999;353:133–8.PubMedGoogle Scholar
  261. 261.
    Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebo-controlled study. Lancet 2001;358:1119–23.PubMedGoogle Scholar
  262. 262.
    Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896–903.PubMedGoogle Scholar
  263. 263.
    McLaughlin VV. Survival in patients with pulmonary arterial hypertension treated with first-line bosentan. Eur J Clin Invest 2006;36 Suppl 3:10–5.PubMedGoogle Scholar
  264. 264.
    Barst RJ, Langleben D, Frost A, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 2004;169:441–7.PubMedGoogle Scholar
  265. 265.
    Barst RJ, Langleben D, Badesch D, et al. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol 2006;47:2049–56.PubMedGoogle Scholar
  266. 266.
  267. 267.
    Rapoport RM, Draznin MB, Murad F. Endothelium-dependent relaxation in rat aorta may be mediated through cyclic GMP-dependent protein phosphorylation. Nature 1983;306:174–6.PubMedGoogle Scholar
  268. 268.
    Sanchez LS, de la Monte SM, Filippov G, Jones RC, Zapol WM, Bloch KD. Cyclic-GMP-binding, cyclic-GMP-specific phosphodiesterase (PDE5) gene expression is regulated during rat pulmonary development. Pediatr Res 1998;43:163–8.PubMedGoogle Scholar
  269. 269.
    Prasad S, Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary hypertension. N Engl J Med 2000;343:1342.PubMedGoogle Scholar
  270. 270.
    Littera R, La Nasa G, Derchi G, Cappellini MD, Chang CY, Contu L. Long-term treatment with sildenafil in a thalassemic patient with pulmonary hypertension. Blood 2002;100:1516–7.PubMedGoogle Scholar
  271. 271.
    Kothari SS, Duggal B. Chronic oral sildenafil therapy in severe pulmonary artery hypertension. Indian Heart J 2002;54:404–9.PubMedGoogle Scholar
  272. 272.
    Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148–57.PubMedGoogle Scholar
  273. 273.
    Klepetko W, Mayer E, Sandoval J, et al. Interventional and surgical modalities of treatment for pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:73S–80S.PubMedGoogle Scholar
  274. 274.
    Selimovic N, Rundqvist B, Bergh CH, et al. Assessment of pulmonary vascular resistance by Doppler echocardiography in patients with pulmonary arterial hypertension. J Heart Lung Transplant 2007;26:927–34.PubMedGoogle Scholar
  275. 275.
    Gurudevan SV, Malouf PJ, Kahn AM, et al. Noninvasive assessment of pulmonary vascular resistance using Doppler tissue imaging of the tricuspid annulus. J Am Soc Echocardiogr 2007;20:1167–71.PubMedGoogle Scholar
  276. 276.
    Sanz J, Kuschnir P, Rius T, et al. Pulmonary arterial hypertension: Noninvasive detection with phase-contrast MR imaging. Radiology 2007;243:70–9.PubMedGoogle Scholar
  277. 277.
    Nagaya N, Nishikimi T, Okano Y, et al. Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol 1998;31:202–8.PubMedGoogle Scholar
  278. 278.
    Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation 2000;102:865–70.PubMedGoogle Scholar
  279. 279.
    Nagaya N, Ando M, Oya H, et al. Plasma brain natriuretic peptide as a noninvasive marker for efficacy of pulmonary thromboendarterectomy. Ann Thorac Surg 2002;74:180–4; discussion 4.PubMedGoogle Scholar
  280. 280.
    Cracowski JL, Yaici A, Sitbon O, et al. Biomarkers as prognostic factors in pulmonary arterial hypertension. Rationale and study design. Rev maladies respiratoires 2004;21:1137–43.Google Scholar
  281. 281.
    Frelin C, Ladoux A, D‘Angelo G. Vascular endothelial growth factors and angiogenesis. Annales d‘endocrinol 2000;61:70–4.Google Scholar
  282. 282.
    Geiger R, Berger RM, Hess J, Bogers AJ, Sharma HS, Mooi WJ. Enhanced expression of vascular endothelial growth factor in pulmonary plexogenic arteriopathy due to congenital heart disease. J Pathol 2000;191:202–7.PubMedGoogle Scholar
  283. 283.
    Hirose S, Hosoda Y, Furuya S, Otsuki T, Ikeda E. Expression of vascular endothelial growth factor and its receptors correlates closely with formation of the plexiform lesion in human pulmonary hypertension. Pathol Int 2000;50:472–9.PubMedGoogle Scholar
  284. 284.
    Mata-Greenwood E, Meyrick B, Soifer SJ, Fineman JR, Black SM. Expression of VEGF and its receptors Flt-1 and Flk-1/KDR is altered in lambs with increased pulmonary blood flow and pulmonary hypertension. Am J Physiol 2003;285:L222–31.Google Scholar
  285. 285.
    Michelakis ED, McMurtry MS, Wu XC, et al. 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;105:244–50.PubMedGoogle Scholar
  286. 286.
    Nagaya N, Uematsu M, Oya H, et al. Short-term oral administration of L-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension. Am J Respir Crit Care Med 2001;163:887–91.PubMedGoogle Scholar
  287. 287.
    Nishimura T, Faul JL, Berry GJ, et al. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am J Respir Crit Care Med 2002;166:1403–8.PubMedGoogle Scholar
  288. 288.
    Nishimura T, Vaszar LT, Faul JL, et al. Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation 2003;108:1640–5.PubMedGoogle Scholar
  289. 289.
    Hironaka E, Hongo M, Sakai A, et al. Serotonin receptor antagonist inhibits monocrotaline-induced pulmonary hypertension and prolongs survival in rats. Cardiovasc Res 2003;60:692–9.PubMedGoogle Scholar
  290. 290.
    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.PubMedGoogle Scholar
  291. 291.
    Nagaya N, Miyatake K, Kyotani S, Nishikimi T, Nakanishi N, Kangawa K. Pulmonary vasodilator response to adrenomedullin in patients with pulmonary hypertension. Hypertens Res 2003;26 Suppl:S141–6.PubMedGoogle Scholar
  292. 292.
    Nakanishi K, Osada H, Uenoyama M, et al. Expressions of adrenomedullin mRNA and protein in rats with hypobaric hypoxia-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 2004;286:H2159–68.PubMedGoogle Scholar
  293. 293.
    Upton PD, Wharton J, Coppock H, et al. Adrenomedullin expression and growth inhibitory effects in distinct pulmonary artery smooth muscle cell subpopulations. Am J Respir Cell Mol Biol 2001;24:170–8.PubMedGoogle Scholar
  294. 294.
    Vijay P. Adrenomedullin in the treatment of pulmonary hypertension. Heart (Br Cardiac Soc) 2000;84:575–6.Google Scholar
  295. 295.
    Hunter CJ, Dejam A, Blood AB, et al. Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. Nat Med 2004;10:1122–7.PubMedGoogle Scholar
  296. 296.
    Muehlschlegel JD, Lobato EB, Kirby DS, Arnaoutakis G, Sidi A. Inhaled amyl nitrite effectively reverses acute catastrophic thromboxane-mediated pulmonary hypertension in pigs. Ann Card Anaesth 2007;10:113–20.PubMedGoogle Scholar
  297. 297.
    Crossno JT, Jr., Garat CV, Reusch JE, et al. Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling. Am J Physiol 2007;292:L885–97.Google Scholar
  298. 298.
    O‘Callaghan D, Gaine SP. Combination therapy and new types of agents for pulmonary arterial hypertension. Clin Chest Med 2007;28:169–85, ix.PubMedGoogle Scholar
  299. 299.
    Rosenzweig EB. Emerging treatments for pulmonary arterial hypertension. Exp Opin Emerg Drugs 2006;11:609–19.Google Scholar
  300. 300.
    Platoshyn O, Yu Y, Golovina VA, et al. Chronic hypoxia decreases K(V) channel expression and function in pulmonary artery myocytes. Am J Physiol 2001;280:L801–12.Google Scholar
  301. 301.
    Koh KK. Effects of statins on vascular wall: Vasomotor function, inflammation, and plaque stability. Cardiovasc Res 2000;47:648–57.PubMedGoogle Scholar
  302. 302.
    Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000;6:1399–402.PubMedGoogle Scholar
  303. 303.
    Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998;97:1129–35.PubMedGoogle Scholar
  304. 304.
    Laufs U, Fata VL, Liao JK. Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. J Biol Chem 1997;272:31725–9.PubMedGoogle Scholar
  305. 305.
    Cai Y, Han M, Luo L, Song W, Zhou X. Increased expression of PDGF and c-myc genes in lungs and pulmonary arteries of pulmonary hypertensive rats induced by hypoxia. Chinese Med Sci J = Chung-kuo i hsueh k‘o hsueh tsa chih/Chinese Acad Med Sci 1996;11:152–6.Google Scholar
  306. 306.
    Souza R, Sitbon O, Parent F, Simonneau G, Humbert M. Long term imatinib treatment in pulmonary arterial hypertension. Thorax 2006;61:736.PubMedGoogle Scholar
  307. 307.
    Patterson KC, Weissmann A, Ahmadi T, Farber HW. Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension. Ann Intern Med 2006;145:152–3.PubMedGoogle Scholar
  308. 308.
    Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 2005;353:1412–3.PubMedGoogle Scholar
  309. 309.
    Hirschhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005;6:95–108.PubMedGoogle Scholar
  310. 310.
    Wang WY, Barratt BJ, Clayton DG, Todd JA. Genome-wide association studies: Theoretical and practical concerns. Nat Rev Genet 2005;6:109–18.PubMedGoogle Scholar
  311. 311.
    Frid MG, Kale VA, Stenmark KR. Mature vascular endothelium can give rise to smooth muscle cells via endothelial–mesenchymal transdifferentiation: In vitro analysis. Circ Res 2002;90:1189–96.PubMedGoogle Scholar
  312. 312.
    Nagaya N, Kangawa K, Kanda M, et al. Hybrid cell-gene therapy for pulmonary hypertension based on phagocytosing action of endothelial progenitor cells. Circulation 2003;108:889–95.PubMedGoogle Scholar
  313. 313.
    Satoh K, Kagaya Y, Nakano M, et al. Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice. Circulation 2006;113:1442–50.PubMedGoogle Scholar
  314. 314.
    Stewart DJ, Zhao YD, Courtman DW. Cell therapy for pulmonary hypertension: What is the true potential of endothelial progenitor cells? Circulation 2004; 109:e172–3; author reply e–3.PubMedGoogle Scholar
  315. 315.
    Takahashi M, Nakamura T, Toba T, Kajiwara N, Kato H, Shimizu Y. Transplantation of endothelial progenitor cells into the lung to alleviate pulmonary hypertension in dogs. Tissue Eng 2004;10:771–9.PubMedGoogle Scholar
  316. 316.
    Wang XX, Zhang FR, Shang YP, et al. Transplantation of autologous endothelial progenitor cells may be beneficial in patients with idiopathic pulmonary arterial hypertension: A pilot randomized controlled trial. J Am Coll Cardiol 2007;49:1566–71.PubMedGoogle Scholar
  317. 317.
    Zeng C, Wang X, Hu X, Chen J, Wang L. Autologous endothelial progenitor cells transplantation for the therapy of primary pulmonary hypertension. Med Hypotheses 2007;68:1292–5.PubMedGoogle Scholar
  318. 318.
    Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: Efficacy of combined cell and eNOS gene therapy in established disease. Circ Res 2005;96:442–50.PubMedGoogle Scholar
  319. 319.
    The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. Boston, MA: Little, Brown & Co, 9th Ed. 1994; 253–6.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Jean M. Elwing
    • 1
  • Gail H. Deutsch
    • 2
  • William C. Nichols
    • 3
  • Timothy D. Le Cras
    • 3
  1. 1.Department of Internal MedicineUniversity of Cincinnati School of MedicineCincinnatiUSA
  2. 2.Department of PathologySeattle Children’s HospitalSeattleUSA
  3. 3.Department of PediatricsUniversity of Cincinnati School of Medicine and Cincinnati Children’s Hospital Medical CenterCincinnatiUSA

Personalised recommendations