Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of disease: pulmonary arterial hypertension

Nature Reviews Cardiology volume 8, pages 443–455 (2011)Cite this article

Subjects

Abstract

Our understanding of, and approach to, pulmonary arterial hypertension has undergone a paradigm shift in the past decade. Once a condition thought to be dominated by increased vasoconstrictor tone and thrombosis, pulmonary arterial hypertension is now seen as a vasculopathy in which structural changes driven by excessive vascular cell growth and inflammation, with recruitment and infiltration of circulating cells, play a major role. Perturbations of a number of molecular mechanisms have been described, including pathways involving growth factors, cytokines, metabolic signaling, elastases, and proteases, that may underlie the pathogenesis of the disease. Elucidating their contribution to the pathophysiology of pulmonary arterial hypertension could offer new drug targets. The role of progenitor cells in vascular repair is also under active investigation. The right ventricular response to increased pressure load is recognized as critical to survival and the molecular mechanisms involved are attracting increasing interest. The challenge now is to integrate this new knowledge and explore how it can be used to categorize patients by molecular phenotype and tailor treatment more effectively.

Key Points

  • Pulmonary hypertension is a progressive disease of various origins, which has a poor prognosis and affects, in its different forms, more than 100 million people worldwide

  • Pulmonary arterial hypertension (PAH) is now considered to be a vasculopathy in which structural changes driven by excessive vascular cell growth and inflammation have a major role

  • A number of proproliferative signaling pathways involving growth factors, cytokines, metabolic signaling, and elastases and proteases have been identified in the pathophysiology of PAH

  • Clinical studies with tyrosine kinase inhibitors, serotonin antagonists, and soluble guanylate cyclase stimulators are underway in patients with PAH

  • The benefits of progenitor cells for vascular repair in PAH are under active investigation

  • The right ventricular response to increased pressure load is recognized as critical to survival in patients with PAH, and strategies for preserving myocardial function are increasingly attracting interest

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Vascular remodeling in pulmonary arterial hypertension.
Figure 2: Growth factor signaling in pulmonary arterial hypertension.
Figure 3: Notch signaling pathway and its proposed role in pulmonary hypertension.
Figure 4: Inflammation-mediated vascular remodeling in PAH.
Figure 5: Metabolic pathways in the mitochondrion.

Similar content being viewed by others

References

  1. Simonneau, G. et al. Updated clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. 54, S43–S54 (2009).

    PubMed  Google Scholar 

  2. dos Santos Fernandes, C. J. et al. Survival in schistosomiasis-associated pulmonary arterial hypertension. J. Am. Coll. Cardiol. 56, 715–720 (2010).

    PubMed  Google Scholar 

  3. Graham, B. B., Bandeira, A. P., Morrell, N. W., Butrous, G. & Tuder, R. M. Schistosomiasis-associated pulmonary hypertension: pulmonary vascular disease: the global perspective. Chest 137, 20S–29S (2010).

    PubMed  Google Scholar 

  4. Lapa, M. et al. Cardiopulmonary manifestations of hepatosplenic schistosomiasis. Circulation 119, 1518–1523 (2009).

    PubMed  Google Scholar 

  5. Butrous, G., Ghofrani, H. A. & Grimminger, F. Pulmonary vascular disease in the developing world. Circulation 118, 1758–1766 (2008).

    PubMed  Google Scholar 

  6. Stenmark, K. R., Meyrick, B., Galie, N., Mooi, W. J. & McMurtry, I. F. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, L1013–L1032 (2009).

    CAS  PubMed  Google Scholar 

  7. Tuder, R. M. et al. Development and pathology of pulmonary hypertension. J. Am. Coll. Cardiol. 54, S3–S9 (2009).

    CAS  PubMed  Google Scholar 

  8. Fourie, P. R., Coetzee, A. R. & Bolliger, C. T. Pulmonary artery compliance: its role in right ventricular-arterial coupling. Cardiovasc. Res. 26, 839–844 (1992).

    CAS  PubMed  Google Scholar 

  9. Rabinovitch, M. Pathobiology of pulmonary hypertension. Annu. Rev. Pathol. 2, 369–399 (2007).

    CAS  PubMed  Google Scholar 

  10. Frid, M. G. et al. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am. J. Pathol. 168, 659–669 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhao, Y. D. et al. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ. Res. 96, 442–450 (2005).

    CAS  PubMed  Google Scholar 

  12. Christman, B. W. et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N. Engl. J. Med. 327, 70–75 (1992).

    CAS  PubMed  Google Scholar 

  13. Kreymborg, K. et al. Identification of right heart-enriched genes in a murine model of chronic outflow tract obstruction. J. Mol. Cell. Cardiol. 49, 598–605 (2010).

    CAS  PubMed  Google Scholar 

  14. Ghofrani, H. A., Osterloh, I. H. & Grimminger, F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat. Rev. Drug Discov. 5, 689–702 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Wharton, J. et al. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am. J. Respir. Crit. Care Med. 172, 105–113 (2005).

    PubMed  Google Scholar 

  16. Leiper, J. et al. Disruption of methylarginine metabolism impairs vascular homeostasis. Nat. Med. 13, 198–203 (2007).

    CAS  PubMed  Google Scholar 

  17. Pullamsetti, S. et al. Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension. FASEB J. 19, 1175–1177 (2005).

    CAS  PubMed  Google Scholar 

  18. Launay, J. M. et al. Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat. Med. 8, 1129–1135 (2002).

    CAS  PubMed  Google Scholar 

  19. Eddahibi, S. et al. Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: critical role for serotonin-induced smooth muscle hyperplasia. Circulation 113, 1857–1864 (2006).

    CAS  PubMed  Google Scholar 

  20. Uchida, S. et al. An integrated approach for the systematic identification and characterization of heart-enriched genes with unknown functions. BMC Genomics 10, 100 (2009).

    PubMed  PubMed Central  Google Scholar 

  21. Yuan, X. J., Wang, J., Juhaszova, M., Gaine, S. P. & Rubin, L. J. Attenuated K+ channel gene transcription in primary pulmonary hypertension. Lancet 351, 726–727 (1998).

    CAS  PubMed  Google Scholar 

  22. Mandegar, M. & Yuan, J. X. Role of K+ channels in pulmonary hypertension. Vascul. Pharmacol. 38, 25–33 (2002).

    CAS  PubMed  Google Scholar 

  23. Moudgil, R., Michelakis, E. D. & Archer, S. L. The role of K+ channels in determining pulmonary vascular tone, oxygen sensing, cell proliferation, and apoptosis: Implications in hypoxic pulmonary vasoconstriction and pulmonary arterial hypertension. Microcirculation 13, 615–632 (2006).

    CAS  PubMed  Google Scholar 

  24. Yu, Y. et al. Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Proc. Natl Acad. Sci. U.S.A. 101, 13861–13866 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Weissmann, N. et al. Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Proc. Natl Acad. Sci. U.S.A. 103, 19093–19098 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Davie, N. et al. ETA and ETB receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am. J. Respir. Crit. Care Med. 165, 398–405 (2002).

    PubMed  Google Scholar 

  27. Burg, E. D., Remillard, C. V. & Yuan, J. X. Potassium channels in the regulation of pulmonary artery smooth muscle cell proliferation and apoptosis: pharmacotherapeutic implications. Br. J. Pharmacol. 153, S99–S111 (2008).

    CAS  PubMed  Google Scholar 

  28. Tabima, D. M. & Chesler, N. C. The effects of vasoactivity and hypoxic pulmonary hypertension on extralobar pulmonary artery biomechanics. J. Biomech. 43, 1864–1869 (2010).

    PubMed  PubMed Central  Google Scholar 

  29. Tozzi, C. A., Christiansen, D. L., Poiani, G. J. & Riley, D. J. Excess collagen in hypertensive pulmonary arteries decreases vascular distensibility. Am. J. Respir. Crit. Care Med. 149, 1317–1326 (1994).

    CAS  PubMed  Google Scholar 

  30. Ooi, C. Y., Wang, Z., Tabima, D. M., Eickhoff, J. C. & Chesler, N. C. The role of collagen in extralobar pulmonary artery stiffening in response to hypoxia-induced pulmonary hypertension. Am. J. Physiol. Heart Circ. Physiol. 299, H1823–H1831 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Geiger, R. et al. Enhanced expression of vascular endothelial growth factor in pulmonary plexogenic arteriopathy due to congenital heart disease. J. Pathol. 191, 202–207 (2000).

    CAS  PubMed  Google Scholar 

  32. Tuder, R. M. et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J. Pathol. 195, 367–374 (2001).

    CAS  PubMed  Google Scholar 

  33. Partovian, C. et al. Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertension. Am. J. Physiol. 275, H1948–H1956 (1998).

    CAS  PubMed  Google Scholar 

  34. Partovian, C. et al. Cardiac and lung VEGF mRNA expression in chronically hypoxic and monocrotaline-treated rats. Chest 114, 45S–46S (1998).

    CAS  PubMed  Google Scholar 

  35. Kasahara, Y. et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J. Clin. Invest. 106, 1311–1319 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Tuder, R. M. et al. Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade. Am. J. Respir. Cell Mol. Biol. 29, 88–97 (2003).

    CAS  PubMed  Google Scholar 

  37. Taraseviciene-Stewart, 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. 15, 427–438 (2001).

    CAS  PubMed  Google Scholar 

  38. Taraseviciene-Stewart, L. et al. Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L668–L676 (2006).

    CAS  PubMed  Google Scholar 

  39. Campbell, A. I., Zhao, Y., Sandhu, R. & Stewart, D. J. Cell-based gene transfer of vascular endothelial growth factor attenuates monocrotaline-induced pulmonary hypertension. Circulation 104, 2242–2248 (2001).

    CAS  PubMed  Google Scholar 

  40. Farkas, L. et al. VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats. J. Clin. Invest. 119, 1298–1311 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Partovian, C. et al. Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats. Am. J. Respir. Cell Mol. Biol. 23, 762–771 (2000).

    CAS  PubMed  Google Scholar 

  42. Klein, M. et al. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation 118, 2081–2090 (2008).

    CAS  PubMed  Google Scholar 

  43. Moreno-Vinasco, L. et al. Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension. Physiol. Genomics 33, 278–291 (2008).

    CAS  PubMed  Google Scholar 

  44. Tuder, R. M. & Yun, J. H. Vascular endothelial growth factor of the lung: friend or foe. Curr. Opin. Pharmacol. 8, 255–260 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Benisty, J. I. et al. Elevated basic fibroblast growth factor levels in patients with pulmonary arterial hypertension. Chest 126, 1255–1261 (2004).

    CAS  PubMed  Google Scholar 

  46. Li, P., Oparil, S., Sun, J. Z., Thompson, J. A. & Chen, Y. F. Fibroblast growth factor mediates hypoxia-induced endothelin-- a receptor expression in lung artery smooth muscle cells. J. Appl. Physiol. 95, 643–651 (2003).

    CAS  PubMed  Google Scholar 

  47. Quinn, T. P., Schlueter, M., Soifer, S. J. & Gutierrez, J. A. Cyclic mechanical stretch induces VEGF and FGF-2 expression in pulmonary vascular smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 282, L897–L903 (2002).

    CAS  PubMed  Google Scholar 

  48. Wedgwood, S. et al. Fibroblast growth factor 2 expression is altered in lambs with increased pulmonary blood flow and pulmonary hypertension. Pediatr. Res. 61, 32–36 (2007).

    CAS  PubMed  Google Scholar 

  49. Kwapiszewska, G. et al. Expression profiling of laser-microdissected intrapulmonary arteries in hypoxia-induced pulmonary hypertension. Respir. Res. 6, 109 (2005).

    PubMed  PubMed Central  Google Scholar 

  50. Izikki, M. et al. Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J. Clin. Invest 119, 512–523 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Le Cras, T. D., Hardie, W. D., Fagan, K., Whitsett, J. A. & Korfhagen, T. R. Disrupted pulmonary vascular development and pulmonary hypertension in transgenic mice overexpressing transforming growth factor-alpha. Am. J. Physiol. Lung Cell. Mol. Physiol. 285, L1046–L1054 (2003).

    CAS  PubMed  Google Scholar 

  52. Jones, P. L. & 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. 79, 1131–1142 (1996).

    CAS  PubMed  Google Scholar 

  53. Schultz, K., Fanburg, B. L. & Beasley, D. Hypoxia and hypoxia-inducible factor-1alpha promote growth factor-induced proliferation of human vascular smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol. 290, H2528–H2534 (2006).

    CAS  PubMed  Google Scholar 

  54. Dahal, B. K. et al. Role of epidermal growth factor inhibition in experimental pulmonary hypertension. Am. J. Respir. Crit. Care Med. 181, 158–167 (2010).

    CAS  PubMed  Google Scholar 

  55. Merklinger, S. L., Jones, P. L., Martinez, E. C. & Rabinovitch, M. Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 112, 423–431 (2005).

    CAS  PubMed  Google Scholar 

  56. Grimminger, F. & Schermuly, R. T. PDGF receptor and its antagonists: role in treatment of PAH. Adv. Exp. Med. Biol. 661, 435–446 (2010).

    CAS  PubMed  Google Scholar 

  57. Yu, Y. et al. PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression. Am. J. Physiol. Cell Physiol. 284, C316–C330 (2003).

    CAS  PubMed  Google Scholar 

  58. Humbert, M. et al. Platelet-derived growth factor expression in primary pulmonary hypertension: comparison of HIV seropositive and HIV seronegative patients. Eur. Respir. J. 11, 554–559 (1998).

    CAS  PubMed  Google Scholar 

  59. Schermuly, R. T. et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J. Clin. Invest. 115, 2811–2821 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Perros, F. et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 178, 81–88 (2008).

    CAS  PubMed  Google Scholar 

  61. Cohen, E. D. et al. Wnt signaling regulates smooth muscle precursor development in the mouse lung via a tenascin C/PDGFR pathway. J. Clin. Invest 119, 2538–2549 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Balasubramaniam, V. et al. Role of platelet-derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus. Am. J. Physiol. Lung Cell Mol. Physiol. 284, L826–L833 (2003).

    CAS  PubMed  Google Scholar 

  63. Hayashi, S. et al. Potential role of hepatocyte growth factor, a novel angiogenic growth factor, in peripheral arterial disease: downregulation of HGF in response to hypoxia in vascular cells. Circulation 100, II301–II308 (1999).

    CAS  PubMed  Google Scholar 

  64. Ono, M. et al. Hepatocyte growth factor suppresses vascular medial hyperplasia and matrix accumulation in advanced pulmonary hypertension of rats. Circulation 110, 2896–2902 (2004).

    CAS  PubMed  Google Scholar 

  65. Ono, M. et al. Gene transfer of hepatocyte growth factor with prostacyclin synthase in severe pulmonary hypertension of rats. Eur. J. Cardiothorac. Surg. 26, 1092–1097 (2004).

    PubMed  Google Scholar 

  66. Machado, R. D. et al. Genetics and genomics of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 54, S32–S42 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Heath, D. & Yacoub, M. Lung mast cells in plexogenic pulmonary arteriopathy. J. Clin. Pathol. 44, 1003–1006 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Mitani, Y. et al. Mast cell chymase in pulmonary hypertension. Thorax 54, 88–90 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Nicolls, M. R., Taraseviciene-Stewart, L., Rai, P. R., Badesch, D. B. & Voelkel, N. F. Autoimmunity and pulmonary hypertension: a perspective. Eur. Respir. J. 26, 1110–1118 (2005).

    CAS  PubMed  Google Scholar 

  70. Tucker, A., McMurtry, I. F., Alexander, A. F., Reeves, J. T. & Grover, R. F. Lung mast cell density and distribution in chronically hypoxic animals. J. Appl. Physiol. 42, 174–178 (1977).

    CAS  PubMed  Google Scholar 

  71. Rabinovitch, M. Elastase and the pathobiology of unexplained pulmonary hypertension. Chest 114, 213S–224S (1998).

    CAS  PubMed  Google Scholar 

  72. Lepetit, H. et al. Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension. Eur. Respir. J. 25, 834–842 (2005).

    CAS  PubMed  Google Scholar 

  73. Benisty, J. I. et al. Matrix metalloproteinases in the urine of patients with pulmonary arterial hypertension. Chest 128 (Suppl. 6), 572S (2005).

    PubMed  Google Scholar 

  74. Cowan, K. N. et al. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. J. Am. Coll. Cardiol. 35, 545A–545A (2000).

    Google Scholar 

  75. Cowan, K. N., Jones, P. L. & Rabinovitch, M. Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J. Clin. Invest. 105, 21–34 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Lane, K. B. et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat. Genet. 26, 81–84 (2000).

    CAS  PubMed  Google Scholar 

  77. Deng, Z. et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am. J. Hum. Genet. 67, 737–744 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Trembath, R. C. et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N. Engl. J. Med. 345, 325–334 (2001).

    CAS  PubMed  Google Scholar 

  79. Rudarakanchana, N. et al. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum. Mol. Genet. 11, 1517–1525 (2002).

    CAS  PubMed  Google Scholar 

  80. Yang, X. et al. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ. Res. 96, 1053–1063 (2005).

    CAS  PubMed  Google Scholar 

  81. Machado, R. D. et al. Functional interaction between BMPR-II and Tctex-1, a light chain of Dynein, is isoform-specific and disrupted by mutations underlying primary pulmonary hypertension. Hum. Mol. Genet. 12, 3277–3286 (2003).

    CAS  PubMed  Google Scholar 

  82. Foletta, V. C. et al. Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1. J. Cell Biol. 162, 1089–1098 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Eickelberg, O. & Morty, R. E. Transforming growth factor beta/bone morphogenic protein signaling in pulmonary arterial hypertension: Remodeling revisited. Trends Cardiovasc. Med. 17, 263–269 (2007).

    CAS  PubMed  Google Scholar 

  84. Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776 (1999).

    CAS  PubMed  Google Scholar 

  85. Alva, J. A. & Iruela-Arispe, M. L. Notch signaling in vascular morphogenesis. Curr. Opin. Hematol. 11, 278–283 (2004).

    CAS  PubMed  Google Scholar 

  86. Villa, N. et al. Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech. Dev. 108, 161–164 (2001).

    CAS  PubMed  Google Scholar 

  87. Domenga, V. et al. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev. 18, 2730–2735 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Proweller, A., Pear, W. S. & Parmacek, M. S. Notch signaling represses myocardin-induced smooth muscle cell differentiation. J. Biol. Chem. 280, 8994–9004 (2005).

    CAS  PubMed  Google Scholar 

  89. Campos, A. H., Wang, W., Pollman, M. J. & Gibbons, G. H. Determinants of Notch-3 receptor expression and signaling in vascular smooth muscle cells: implications in cell-cycle regulation. Circ. Res. 91, 999–1006 (2002).

    CAS  PubMed  Google Scholar 

  90. Gustafsson, M. V. et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev. Cell 9, 617–628 (2005).

    CAS  PubMed  Google Scholar 

  91. Jin, S. et al. Notch signaling regulates platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells. Circ. Res. 102, 1483–1491 (2008).

    CAS  PubMed  Google Scholar 

  92. Li, X. D. et al. Notch3 signaling promotes the development of pulmonary arterial hypertension. Nat. Med. 15, 1289–1297 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Issemann, I. & Green, S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347, 645–650 (1990).

    CAS  PubMed  Google Scholar 

  94. Rios-Vazquez, R., Marzoa-Rivas, R., Gil-Ortega, I. & Kaski, J. C. Peroxisome proliferator-activated receptor-gamma agonists for management and prevention of vascular disease in patients with and without diabetes mellitus. Am. J. Cardiovasc. Drugs 6, 231–242 (2006).

    CAS  PubMed  Google Scholar 

  95. Duan, S. Z., Usher, M. G. & Mortensen, R. M. Peroxisome proliferator-activated receptor-gamma-mediated effects in the vasculature. Circ. Res. 102, 283–294 (2008).

    CAS  PubMed  Google Scholar 

  96. Chinetti, G. et al. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J. Biol. Chem. 273, 25573–25580 (1998).

    CAS  PubMed  Google Scholar 

  97. Jiang, C., Ting, A. T. & Seed, B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 391, 82–86 (1998).

    CAS  PubMed  Google Scholar 

  98. Panigrahy, D. et al. PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. J. Clin. Invest. 110, 923–932 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Takeda, K., Ichiki, T., Tokunou, T., Iino, N. & Takeshita, A. 15-Deoxy-delta 12,14-prostaglandin J2 and thiazolidinediones activate the MEK/ERK pathway through phosphatidylinositol 3-kinase in vascular smooth muscle cells. J. Biol. Chem. 276, 48950–48955 (2001).

    CAS  PubMed  Google Scholar 

  100. Spiegelman, B. M. & Flier, J. S. Adipogenesis and obesity: rounding out the big picture. Cell 87, 377–389 (1996).

    CAS  PubMed  Google Scholar 

  101. Ameshima, S. et al. Peroxisome proliferator-activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ. Res. 92, 1162–1169 (2003).

    CAS  PubMed  Google Scholar 

  102. Barak, Y. et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol. Cell 4, 585–595 (1999).

    CAS  PubMed  Google Scholar 

  103. Hansmann, G. et al. An antiproliferative BMP-2/PPARgamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension. J. Clin. Invest. 118, 1846–1857 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Guignabert, C. et al. Tie2-mediated loss of peroxisome proliferator-activated receptor-gamma in mice causes PDGF receptor-beta-dependent pulmonary arterial muscularization. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, L1082–L1090 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Hansmann, G. et al. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation. Circulation 115, 1275–1284 (2007).

    CAS  PubMed  Google Scholar 

  106. Martin-Nizard, F. et al. Peroxisome proliferator-activated receptor activators inhibit oxidized low-density lipoprotein-induced endothelin-1 secretion in endothelial cells. J. Cardiovasc. Pharmacol. 40, 822–831 (2002).

    CAS  PubMed  Google Scholar 

  107. Wakino, S. et al. Pioglitazone lowers systemic asymmetric dimethylarginine by inducing dimethylarginine dimethylaminohydrolase in rats. Hypertens. Res. 28, 255–262 (2005).

    CAS  PubMed  Google Scholar 

  108. Kielstein, J. T. et al. Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler. Thromb. Vasc. Biol. 25, 1414–1418 (2005).

    CAS  PubMed  Google Scholar 

  109. Li, M. et al. Heme oxygenase-1/p21WAF1 mediates peroxisome proliferator-activated receptor-gamma signaling inhibition of proliferation of rat pulmonary artery smooth muscle cells. FEBS J. 277, 1543–1550 (2010).

    CAS  PubMed  Google Scholar 

  110. Matsuda, Y. et al. Effects of peroxisome proliferator-activated receptor gamma ligands on monocrotaline-induced pulmonary hypertension in rats [Japanese]. Nihon Kokyuki Gakkai Zasshi 43, 283–238 (2005).

    PubMed  Google Scholar 

  111. Crossno, J. T., Jr et al. Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling. Am. J. Physiol. Lung Cell Mol. Physiol. 292, L885–L897 (2007).

    CAS  PubMed  Google Scholar 

  112. Nisbet, R. E. et al. Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model. Am. J. Respir. Cell Mol. Biol. 42, 482–490 (2010).

    PubMed  Google Scholar 

  113. Juurlink, D. N. et al. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ 339, b2942 (2009).

    PubMed  PubMed Central  Google Scholar 

  114. Khakoo, A. Y. & Finkel, T. Endothelial progenitor cells. Annu. Rev. Med. 56, 79–101 (2005).

    CAS  PubMed  Google Scholar 

  115. Asahara, T. & Kawamoto, A. Endothelial progenitor cells for postnatal vasculogenesis. Am. J. Physiol. Cell Physiol. 287, C572–C579 (2004).

    CAS  PubMed  Google Scholar 

  116. Tuder, R. M., Groves, B., Badesch, D. B. & Voelkel, N. F. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am. J. Pathol. 144, 275–285 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Spees, J. L. et al. Bone marrow progenitor cells contribute to repair and remodeling of the lung and heart in a rat model of progressive pulmonary hypertension. FASEB J. 22, 1226–1236 (2008).

    CAS  PubMed  Google Scholar 

  118. Hayashida, K. et al. Bone marrow-derived cells contribute to pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension. Chest 127, 1793–1798 (2005).

    PubMed  Google Scholar 

  119. Angelini, D. J. et al. Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELM alpha) recruits bone marrow-derived cells to the murine pulmonary vasculature. PLoS ONE 5, e11251 (2010).

    PubMed  PubMed Central  Google Scholar 

  120. Frid, M. G. et al. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am. J. Pathol. 168, 659–669 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Satoh, K. et al. Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice. Circulation 113, 1442–1450 (2006).

    CAS  PubMed  Google Scholar 

  122. Sahara, M. et al. Diverse contribution of bone marrow-derived cells to vascular remodeling associated with pulmonary arterial hypertension and arterial neointimal formation. Circulation 115, 509–517 (2007).

    PubMed  Google Scholar 

  123. Marsboom, G. et al. Sustained endothelial progenitor cell dysfunction after chronic hypoxia-induced pulmonary hypertension. Stem Cells 26, 1017–1026 (2008).

    PubMed  Google Scholar 

  124. Diller, G. P. et al. Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation 117, 3020–3030 (2008).

    CAS  PubMed  Google Scholar 

  125. Junhui, Z. et al. Reduced number and activity of circulating endothelial progenitor cells in patients with idiopathic pulmonary arterial hypertension. Respir. Med. 102, 1073–1079 (2008).

    PubMed  Google Scholar 

  126. Toshner, M. et al. Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 180, 780–787 (2009).

    PubMed  PubMed Central  Google Scholar 

  127. Asosingh, K. et al. Circulating angiogenic precursors in idiopathic pulmonary arterial hypertension. Am. J. Pathol. 172, 615–627 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. de Jesus Perez, V. A. et al. Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-beta-catenin and Wnt-RhoA-Rac1 pathways. J. Cell Biol. 184, 83–99 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Howell, K., Costello, C. M., 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. 296, L1042–L1050 (2009).

    CAS  PubMed  Google Scholar 

  130. Zhao, Y. D. et al. Microvascular regeneration in established pulmonary hypertension by angiogenic gene transfer. Am. J. Respir. Cell Mol. Biol. 35, 182–189 (2006).

    CAS  PubMed  Google Scholar 

  131. Teng, R. J., Eis, A., Bakhutashvili, I., Arul, N. & Konduri, G. G. Increased superoxide production contributes to the impaired angiogenesis of fetal pulmonary arteries with in utero pulmonary hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, L184–L195 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Hassoun, P. M. et al. Inflammation, growth factors, and pulmonary vascular remodeling. J. Am. Coll. Cardiol. 54, S10–S19 (2009).

    CAS  PubMed  Google Scholar 

  133. Pullamsetti, S. S. et al. Inflammation, immunological reaction and role of infection in pulmonary hypertension. Clin. Microbiol. Infect. 17, 7–14 (2011).

    CAS  PubMed  Google Scholar 

  134. Tuder, R. M., Groves, B., Badesch, D. B. & Voelkel, N. F. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am. J. Pathol. 144, 275–285 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Cool, C. D., Kennedy, D., Voelkel, N. F. & Tuder, R. M. Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum. Pathol. 28, 434–442 (1997).

    CAS  PubMed  Google Scholar 

  136. Hamamdzic, D., Kasman, L. M. & LeRoy, E. C. The role of infectious agents in the pathogenesis of systemic sclerosis. Curr. Opin. Rheumatol. 14, 694–698 (2002).

    PubMed  Google Scholar 

  137. Cool, C. D. et al. Expression of human herpesvirus 8 in primary pulmonary hypertension. N. Engl. J. Med. 349, 1113–1122 (2003).

    CAS  PubMed  Google Scholar 

  138. Henke-Gendo, C., Mengel, M., Hoeper, M. M., Alkharsah, K. & Schulz, T. F. Absence of Kaposi's sarcoma-associated herpesvirus in patients with pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 172, 1581–1585 (2005).

    PubMed  Google Scholar 

  139. Shan, B. et al. Activation of proMMP-2 and Src by HHV8 vGPCR in human pulmonary arterial endothelial cells. J. Mol. Cell. Cardiol. 42, 517–525 (2007).

    CAS  PubMed  Google Scholar 

  140. Bull, T. M. et al. Human herpesvirus-8 infection of primary pulmonary microvascular endothelial cells. Am. J. Respir. Cell Mol. Biol. 39, 706–716 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Graham, B. B. et al. Schistosomiasis-induced experimental pulmonary hypertension: role of interleukin-13 signaling. Am. J. Pathol. 177, 1549–1561 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Freitas, T. C., Jung, E. & Pearce, E. J. TGF-beta signaling controls embryo development in the parasitic flatworm Schistosoma mansoni. PLoS Pathog. 3, e52 (2007).

    PubMed  PubMed Central  Google Scholar 

  143. Crosby, A. et al. Pulmonary vascular remodeling correlates with lung eggs and cytokines in murine schistosomiasis. Am. J. Respir. Crit. Care Med. 181, 279–288.

    CAS  PubMed  Google Scholar 

  144. Humbert, M. et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am. J. Respir. Crit. Care Med. 151, 1628–1631 (1995).

    CAS  PubMed  Google Scholar 

  145. Itoh, T. et al. Increased plasma monocyte chemoattractant protein-1 level in idiopathic pulmonary arterial hypertension. Respirology 11, 158–163 (2006).

    PubMed  Google Scholar 

  146. Tuder, R. M. & Voelkel, N. F. Pulmonary hypertension and inflammation. J. Lab. Clin. Med. 132, 16–24 (1998).

    CAS  PubMed  Google Scholar 

  147. Bhargava, A., Kumar, A., Yuan, N., Gewitz, M. H. & Mathew, R. Monocrotaline induces interleukin-6 mRNA expression in rat lungs. Heart Dis. 1, 126–132 (1999).

    CAS  PubMed  Google Scholar 

  148. Miyata, M. et al. Pulmonary hypertension in rats. 2. Role of interleukin-6. Int. Arch. Allergy Immunol. 108, 287–291 (1995).

    CAS  PubMed  Google Scholar 

  149. Steiner, M. K. et al. Interleukin-6 overexpression induces pulmonary hypertension. Circ. Res. 104, 236–244 (2009).

    CAS  PubMed  Google Scholar 

  150. Savale, L. et al. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir. Res. 10, 6 (2009).

    PubMed  PubMed Central  Google Scholar 

  151. Hagen, M. et al. Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am. J. Physiol. Lung Cell Mol. Physiol. 292, L1473–L1479 (2007).

    CAS  PubMed  Google Scholar 

  152. Brock, M. et al. Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway. Circ. Res. 104, 1184–1191 (2009).

    CAS  PubMed  Google Scholar 

  153. Zlotnik, A. & Yoshie, O. Chemokines: a new classification system and their role in immunity. Immunity 12, 121–127 (2000).

    CAS  PubMed  Google Scholar 

  154. Dorfmuller, P. et al. Chemokine RANTES in severe pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 165, 534–539 (2002).

    PubMed  Google Scholar 

  155. Balabanian, K. et al. CX3C chemokine fractalkine in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 165, 1419–1425 (2002).

    PubMed  Google Scholar 

  156. Bazan, J. F. et al. A new class of membrane-bound chemokine with a CX3C motif. Nature 385, 640–644 (1997).

    CAS  PubMed  Google Scholar 

  157. Papadopoulos, E. J. et al. Fractalkine, a CX3C chemokine, is expressed by dendritic cells and is up-regulated upon dendritic cell maturation. Eur. J. Immunol. 29, 2551–2559 (1999).

    CAS  PubMed  Google Scholar 

  158. Fong, A. M. et al. Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow. J. Exp. Med. 188, 1413–1419 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Perros, F. et al. Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension. Eur. Respir. J. 29, 937–943 (2007).

    CAS  PubMed  Google Scholar 

  160. McDermott, D. H. et al. Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circ. Res. 89, 401–407 (2001).

    CAS  PubMed  Google Scholar 

  161. Sanchez, O. et al. Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 176, 1041–1047 (2007).

    CAS  PubMed  Google Scholar 

  162. Tournier, A. et al. Calibrated automated thrombography demonstrates hypercoagulability in patients with idiopathic pulmonary arterial hypertension. Thromb. Res. 126, e418–e422 (2010).

    CAS  PubMed  Google Scholar 

  163. White, R. J. et al. Plexiform-like lesions and increased tissue factor expression in a rat model of severe pulmonary arterial hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L583–L590 (2007).

    CAS  PubMed  Google Scholar 

  164. Johnson, S. R., Granton, J. T. & Mehta, S. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension. Chest 130, 545–552 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  166. Warburg, O. On metabolism of tumors. (Constable, London, 1930).

    Google Scholar 

  167. Xu, W. et al. Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc. Natl Acad. Sci. U.S.A. 104, 1342–1347 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Bonnet, S. et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11, 37–51 (2007).

    CAS  PubMed  Google Scholar 

  169. Michelakis, E. D. 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 105, 244–250 (2002).

    CAS  PubMed  Google Scholar 

  170. McMurtry, M. S. et al. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ. Res. 95, 830–840 (2004).

    CAS  PubMed  Google Scholar 

  171. Guignabert, C. et al. Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22alpha-targeted overexpression of the serotonin transporter. FASEB J. 23, 4135–4147 (2009).

    CAS  PubMed  Google Scholar 

  172. Michelakis, E. D. et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci. Transl. Med. 2, 31ra34 (2010).

    CAS  PubMed  Google Scholar 

  173. US NIH. ClinicalTrials.gov. Dichloroacetate (DCA) for the treatment of pulmonary arterial hypertension [online], (2010).

  174. Oikawa, M. et al. Increased [18F]fluorodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenol. J. Am. Coll. Cardiol. 45, 1849–1855 (2005).

    CAS  PubMed  Google Scholar 

  175. Piao, L. 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. 88, 47–60 (2010).

    CAS  PubMed  Google Scholar 

  176. Piao, L., Marsboom, G. & Archer, S. L. Mitochondrial metabolic adaptation in right ventricular hypertrophy and failure. J. Mol. Med. 88, 1011–1020 (2010).

    CAS  PubMed  Google Scholar 

  177. Bogaard, H. J., Abe, K., Vonk Noordegraaf, A. & Voelkel, N. F. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest 135, 794–804 (2009).

    CAS  PubMed  Google Scholar 

  178. Haworth, S. The cell and molecular biology of right ventricular dysfunction in pulmonary hypertension. Eur. Heart J. 9 (Suppl. H), H10–H16 (2007).

    CAS  Google Scholar 

  179. Pokreisz, P., Marsboom, G. & Janssens, S. Pressure overload-induced right ventricular dysfunction and remodelling in experimental pulmonary hypertension: the right heart revisited. Eur. Heart J. 9 (Suppl. H), H75–H84 (2007).

    Google Scholar 

  180. Gomez, A. et al. Right ventricular ischemia in patients with primary pulmonary hypertension. J. Am. Coll. Cardiol. 38, 1137–1142 (2001).

    CAS  PubMed  Google Scholar 

  181. van Wolferen, S. A. et al. Right coronary artery flow impairment in patients with pulmonary hypertension. Eur. Heart J. 29, 120–127 (2008).

    PubMed  Google Scholar 

  182. Katsumi, A., Orr, A. W., Tzima, E. & Schwartz, M. A. Integrins in mechanotransduction. J. Biol. Chem. 279, 12001–12004 (2004).

    CAS  PubMed  Google Scholar 

  183. Umar, S. et al. Activation of signaling molecules and matrix metalloproteinases in right ventricular myocardium of rats with pulmonary hypertension. Pathol. Res. Pract. 203, 863–872 (2007).

    CAS  PubMed  Google Scholar 

  184. Broderick, T. L. & King, T. M. Upregulation of GLUT-4 in right ventricle of rats with monocrotaline-induced pulmonary hypertension. Med. Sci. Monit. 14, BR261–BR264 (2008).

    PubMed  Google Scholar 

  185. Bogaard, H. J. et al. Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure. Circulation 120, 1951–1960 (2009).

    PubMed  Google Scholar 

  186. Hessel, M., Steendijk, P., den Adel, B., Schutte, C. & van der Laarse, A. Pressure overload-induced right ventricular failure is associated with re-expression of myocardial tenascin-C and elevated plasma tenascin-C levels. Cell Physiol. Biochem. 24, 201–210 (2009).

    CAS  PubMed  Google Scholar 

  187. Kwapiszewska, G. et al. Fhl-1, a new key protein in pulmonary hypertension. Circulation 118, 1183–1194 (2008).

    CAS  PubMed  Google Scholar 

  188. Abdul-Salam, V. B. et al. Identification of plasma protein biomarkers associated with idiopathic pulmonary arterial hypertension. Proteomics 6, 2286–2294 (2006).

    CAS  PubMed  Google Scholar 

  189. Abdul-Salam, V. B. et al. Proteomic analysis of lung tissues from patients with pulmonary arterial hypertension. Circulation 122, 2058–2067 (2010).

    CAS  PubMed  Google Scholar 

  190. Champion, H. C., Michelakis, E. D. & Hassoun, P. M. Comprehensive invasive and noninvasive approach to the right ventricle-pulmonary circulation unit: state of the art and clinical and research implications. Circulation 120, 992–1007 (2009).

    PubMed  Google Scholar 

  191. Sitbon, O. et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 111, 3105–3111 (2005).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, Bad Nauheim, 61231, Germany

    Ralph T. Schermuly

  2. University Hospital Giessen and Marburg, University of Giessen Lung Center, Klinikstrasse 36, Giessen, 35392, Germany

    Hossein A. Ghofrani & Friedrich Grimminger

  3. Division of Experimental Medicine, Centre for Pharmacology and Therapeutics, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK

    Martin R. Wilkins

Authors
  1. Ralph T. Schermuly
    View author publications

    Search author on:PubMed Google Scholar

  2. Hossein A. Ghofrani
    View author publications

    Search author on:PubMed Google Scholar

  3. Martin R. Wilkins
    View author publications

    Search author on:PubMed Google Scholar

  4. Friedrich Grimminger
    View author publications

    Search author on:PubMed Google Scholar

Contributions

All authors contributed to researching data for the article, made a substantial contribution to the discussion of content, wrote, and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Ralph T. Schermuly.

Ethics declarations

Competing interests

R. T. Schermuly declares he has been a consultant for Actelion, Bayer Healthcare, Ergonex, and Solvay Pharmaceuticals, and has received speakers bureau (honoraria) from Actelion, Bayer Healthcare, GlaxoSmithKlein, Lilly, Solvay Pharmaceuticals, and Pfizer. R. T. Schermuly also declares he has received grant/research support from Actelion, Bayer Healthcare, Ergonex, Excellence Cluster Cardiopulmonary System, German Research Foundation, Gilead, Novartis, Solvay Pharmaceuticals, Pfizer, and the University of Giessen and Marburg Lung Center.

H. A. Ghofrani declares he has been a consultant for Bayer Healthcare, Ergonex, GlaxoSmithKlein, Novartis, and Pfizer, and has received speakers bureau (honoraria) from Bayer Healthcare, GlaxoSmithKlein, Novartis, and Pfizer. H. A. Ghofrani also declares he has received grant/research support from Bayer Healthcare, Excellence Cluster Cardiopulmonary System, German Research Foundation, Novartis, Pfizer, and the University of Giessen and Marburg Lung Center.

M. R. Wilkins declares he has been a consultant for Biomarin and Pfizer, has received speakers bureau (honoraria) from Bayer Healthcare, GlaxoSmithKlein, and Pfizer, and has received grant/research support from Biomarin.

F. Grimminger declares he has been a consultant for Bayer Healthcare, has received speakers bureau (honoraria) from Actelion, Encysive, and Pfizer, and has received grant/research support from Actelion, Excellence Cluster Cardiopulmonary System, GlaxoSmithKlein, German Research Foundation, Novartis, Parexel International GmbH, Pfizer, and the University of Giessen and Marburg Lung Center.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schermuly, R., Ghofrani, H., Wilkins, M. et al. Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol 8, 443–455 (2011). https://doi.org/10.1038/nrcardio.2011.87

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/nrcardio.2011.87

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing