Role of Bone Morphogenetic Protein Receptors in the Development of Pulmonary Arterial Hypertension

  • Nicholas W. MorrellEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (volume 661)


The identification of mutations in the bone morphogenetic protein (BMP) type II receptor in the majority of cases of familial pulmonary arterial hypertension (PAH) has provided a focus for researchers studying the complex pathobiology of this condition. Mutations are also found in a proportion of idiopathic PAH cases and it is now emerging that dysfunctional BMP signaling plays a role in other more common forms of PAH, even in the absence of mutations in the gene. Study of the role of BMP signaling in endothelial, smooth muscle cell, progenitor cell and inflammatory cell biology may reveal novel pathways lending themselves to therapeutic intervention in PAH. This chapter summarizes the present status of our understanding of the role of BMPR-II mutations in PAH and indicates future directions for research.


Bone morphogenetic proteins pulmonary hypertension genetics signal transduction vascular biology 


  1. 1.
    Loyd JE, Primm RK, Newman JH (1984) Familial primary pulmonary hypertension: clinical patterns. Am Rev Respir Dis 129:194-197PubMedGoogle Scholar
  2. 2.
    Newman JH, Wheeler L, Lane KB et al (2001) Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med 345:319-324PubMedCrossRefGoogle Scholar
  3. 3.
    Newman JH, Trembath RC, Morse JA et al (2004) Genetic basis of pulmonary arterial hypertension: current understanding and future directions. J Am Coll Cardiol 43:S33-S39CrossRefGoogle Scholar
  4. 4.
    Nichols WC, Koller DL, Slovis B et al (1997) Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31-32. Nat Genet 15:277-280PubMedCrossRefGoogle Scholar
  5. 5.
    The International PPH Consortium, Lane KB, Machado RD, Pauciulo MW et al (2000) Heterozygous germ-line mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension. Nat Genet 26:81-84PubMedCrossRefGoogle Scholar
  6. 6.
    Deng Z, Morse JH, Slager SL et al (2000) Familial primary pulmonary hypertension (Gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67:737-744PubMedCrossRefGoogle Scholar
  7. 7.
    Machado RD, Aldred MA, James V et al (2006) Mutations of the TGF-β type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mut 27:121-132PubMedCrossRefGoogle Scholar
  8. 8.
    Thomson JR, Machado RD, Pauciulo MW et al (2000) Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-β family. J Med Genet 37:741-745PubMedCrossRefGoogle Scholar
  9. 9.
    Aldred M, Vijayakrishnan J, James V et al (2006) BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mut 27:212-213PubMedCrossRefGoogle Scholar
  10. 10.
    Cogan JD, Vnencak-Jones CL, Phillips JA et al (2005) Gross BMPR2 gene rearrangements constitute a new cause for primary pulmonary hypertension. Genet Med 7:169-174PubMedCrossRefGoogle Scholar
  11. 11.
    Miyazono K, Maeda S, Imamura T. (2005) BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev 16:251-263PubMedCrossRefGoogle Scholar
  12. 12.
    Kawabata M, Imamura T, Miyazano K (1998) Signal transduction by bone morphogenetic proteins. Cytokine Growth Factor Rev 9:49-61PubMedCrossRefGoogle Scholar
  13. 13.
    Massagué J, Chen Y-G (2000) Controlling TGF-β signaling. Genes Dev 14:627-644PubMedGoogle Scholar
  14. 14.
    Attisano L, Wrana JL (2002) Signal transduction by the TGF-β superfamily. Science 296:1646-1647PubMedCrossRefGoogle Scholar
  15. 15.
    Rosenzweig BL, Imamura T, Okadome T et al (1995) Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc Natl Acad Sci U S A 92:7632-7636PubMedCrossRefGoogle Scholar
  16. 16.
    Ishikawa T, Yoshioka H, Ohuchi H, Noji S, Nohno T (1995) Truncated type II receptor for BMP-4 induces secondary axial structures in Xenopus embryos. Biochem Biophys Res Commun 216:26-33PubMedCrossRefGoogle Scholar
  17. 17.
    Howe JR, Bair JL, Sayed MG et al (2001) Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 28:184-187PubMedCrossRefGoogle Scholar
  18. 18.
    Lehmann K, Seemann P, Stricker S et al (2003) Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2. Proc Natl Acad Sci U S A 100:12277-12282PubMedCrossRefGoogle Scholar
  19. 19.
    Nickel J, Kotzsch A, Sebald W, Mueller TD (2005) A single residue of GDF-5 defines binding specificity to BMP receptor IB. J Mol Biol 349:933-947PubMedCrossRefGoogle Scholar
  20. 20.
    David L, Mallet C, Mazerbourg S, Feige JJ, Bailly S (2007) Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood 109:1953-1961PubMedCrossRefGoogle Scholar
  21. 21.
    David L, Mallet C, Keramidas M et al (2008) Bone morphogenetic protein-9 is a circulating vascular quiescence factor. Circ Res 102:914-922PubMedCrossRefGoogle Scholar
  22. 22.
    Massagué J, Seoane J, Wotton D (2005) Smad transcription factors. Genes Dev 19:2783-2810PubMedCrossRefGoogle Scholar
  23. 23.
    Shi W, Chen H, Sun J, Chen C, Zhao J, Wang YL et al (2004) Overexpression of Smurf1 negatively regulates mouse embryonic lung branching morphogenesis by specifically reducing Smad1 and Smad5 proteins. Am J Physiol Lung Cell Mol Physiol 286:L293-L300PubMedCrossRefGoogle Scholar
  24. 24.
    Chen HB, Shen J, Ip YT, Xu L (2006) Identification of phosphatases for Smad in the BMP/DPP pathway. Genes Dev 20:648-653PubMedCrossRefGoogle Scholar
  25. 25.
    Nohe A, Keating E, Knaus P, Petersen NO (2004) Signal transduction of bone morphogenetic protein receptors. Cell Signal 16:291-299PubMedCrossRefGoogle Scholar
  26. 26.
    Massagué J (2003) Integration of Smad and MAPK pathways: a link and a linker revisited. Genes Dev 17:2993-2997PubMedCrossRefGoogle Scholar
  27. 27.
    Grimm OH, Gurdon JB (2002) Nuclear exclusion of Smad2 is a mechanism leading to loss of competence. Nat Cell Biol 4:519-522PubMedCrossRefGoogle Scholar
  28. 28.
    Kretzschmar M, Doody J, Massagu J (1997) Opposing BMP and EGF signalling pathways converge on the TGF-β family mediator Smad1. Nature 389:618-622PubMedCrossRefGoogle Scholar
  29. 29.
    Rudarakanchana N, Flanagan JA, Chen H et al (2002) Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet 11:1517-1525PubMedCrossRefGoogle Scholar
  30. 30.
    Nishihara A, Watabe T, Imamura T, Miyazono K (2002) Functional heterogeneity of bone morphogenetic protein receptor-II mutants found in patients with primary pulmonary hypertension. Mol Biol Cell 13:3055-3063PubMedCrossRefGoogle Scholar
  31. 31.
    Sobolewski A, Rudarakanchana N, Upton PD et al (2008) Failure of bone morphogenetic protein receptor trafficking in pulmonary arterial hypertension: potential for rescue. Hum Mol Genet 17:3180-3190PubMedCrossRefGoogle Scholar
  32. 32.
    Yu PB, Beppu H, Kawai N, Li E, Bloch KD (2005) Bone morphogenetic protein (BMP) type II receptor deletion reveals BMP ligand-specific gain of signaling in pulmonary artery smooth muscle cells. J Biol Chem 280:24443-24450PubMedCrossRefGoogle Scholar
  33. 33.
    Long L, MacLean MR, Jeffery TK et al (2006) Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circ Res 98:818-827PubMedCrossRefGoogle Scholar
  34. 34.
    Morrell NW, Yang X, Upton PD et al (2001) Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-β1 and bone morphogenetic proteins. Circulation 104:790-795PubMedCrossRefGoogle Scholar
  35. 35.
    Goumans MJ, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, ten Dijke P (2002) Balancing the activation status of the endothelium via two distinct TGF-β receptors. EMBO J 21:1743-1753PubMedCrossRefGoogle Scholar
  36. 36.
    Goumans MJ, Valdimarsdottir G, Itoh S et al (2003) Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFβ/ALK5 signaling. Mol Cell 12:817-828PubMedCrossRefGoogle Scholar
  37. 37.
    Itoh S, Thorikay M, Kowanetz M et al (2003) Elucidation of Smad requirement in transforming growth factor-β type I receptor-induced responses. J Biol Chem 278:3751-3761PubMedCrossRefGoogle Scholar
  38. 38.
    Atkinson C, Stewart S, Upton PD et al (2002) Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 105:1672-1678PubMedCrossRefGoogle Scholar
  39. 39.
    Du L, Sullivan CC, Chu D et al (2003) Signaling molecules in nonfamilial pulmonary hypertension. N Engl J Med 348:500-509PubMedCrossRefGoogle Scholar
  40. 40.
    Caldwell RL, Gadipatti R, Lane KB, Shepherd VL (2005) HIV-1 TAT represses transcription of the bone morphogenic protein receptor-2 in U937 monocytic cells. J Leukoc Biol 79:192-201PubMedCrossRefGoogle Scholar
  41. 41.
    Hu H, Sung A, Zhao G et al (2006) Simvastatin enhances bone morphogenetic protein receptor type II expression. Biochem Biophys Res Commun 339:59-64PubMedCrossRefGoogle Scholar
  42. 42.
    Yang X, Long L, Southwood M et al (2005) Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res 96:1053-1063PubMedCrossRefGoogle Scholar
  43. 43.
    Rondelet B, Kerbaul F, Van Beneden R et al (2005) Prevention of pulmonary vascular remodeling and of decreased BMPR-2 expression by losartan therapy in shunt-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 289:H2319-H2324PubMedCrossRefGoogle Scholar
  44. 44.
    Takahashi H, Goto N, Kojima Y et al (2006) Downregulation of type II bone morphogenetic protein receptor in hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 290:L450-L458PubMedCrossRefGoogle Scholar
  45. 45.
    Richter A, Yeager ME, Zaiman A, Cool CD, Voelkel NF, Tuder RM (2004) Impaired transforming growth factor-β signaling in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 170:1340-1348PubMedCrossRefGoogle Scholar
  46. 46.
    Botney MD, Bahadori L, Gold LI (1994) Vascular remodelling in primary pulmonary hypertension: potential role for transforming growth factor-beta. Am J Pathol 144:286-295PubMedGoogle Scholar
  47. 47.
    Zhang S, Fantozzi I, Tigno DD et al (2003) Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 285:L740-L754PubMedGoogle Scholar
  48. 48.
    Yang J, Davies RJ, Southwood M et al (2008) Mutations in bone morphogenetic protein type II receptor cause dysregulation of Id gene expression in pulmonary artery smooth muscle cells: implications for familial pulmonary arterial hypertension. Circ Res 102:1212-1221PubMedCrossRefGoogle Scholar
  49. 49.
    Valdimarsdottir G, Goumans MJ, Rosendahl A et al (2002) Stimulation of Id1 expression by bone morphogenetic protein is sufficient and necessary for bone morphogenetic protein-induced activation of endothelial cells. Circulation 106:2263-2270PubMedCrossRefGoogle Scholar
  50. 50.
    Teichert-Kuliszewska K, Kutryk MJB, Kuliszewski MA et al (2006) Bone morphogenetic protein receptor-2 signaling promotes pulmonary arterial endothelial cell survival: implications for loss-of-function mutations in the pathogenesis of pulmonary hypertension. Circ Res 98:209-217PubMedCrossRefGoogle Scholar
  51. 51.
    Beppu H, Kawabata M, Hamamoto T et al (2000) BMP type II receptor is required for gastrulation and early development of mouse embryos. Dev Biol 221:249-258PubMedCrossRefGoogle Scholar
  52. 52.
    Yang X, Castilla LH, Xin X et al (1999) Angiogenesis defects and mesenchymal apoptosis in mice lacking smad5. Development 126:1571-1580PubMedGoogle Scholar
  53. 53.
    Beppu H, Ichinose F, Kawai N et al (2004) BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia. Am J Physiol Lung Cell Mol Physiol 287:L1241-L1247PubMedCrossRefGoogle Scholar
  54. 54.
    Song Y, Jones JE, Beppu H, Keaney JF Jr, Loscalzo J, Zhang YY (2005) Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice. Circulation 112:553-562PubMedCrossRefGoogle Scholar
  55. 55.
    Miyaki M, Iijima T, Konishi M et al (1999) Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. Oncogene 18:3098-3103PubMedCrossRefGoogle Scholar
  56. 56.
    West J, Fagan K, Steudel W et al (2004) Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle. Circ Res 94:1109-1114PubMedCrossRefGoogle Scholar
  57. 57.
    Delot EC, Bahamonde ME, Zhao M, Lyons KM (2003) BMP signaling is required for septation of the outflow tract of the mammalian heart. Development 130:209-220PubMedCrossRefGoogle Scholar
  58. 58.
    Roberts KE, McElroy JJ, Wong WPK et al (2004) BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J 24:371-374PubMedCrossRefGoogle Scholar
  59. 59.
    Hong K-H, Lee YJ, Lee E et al (2008) Genetic ablation of the Bmpr2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension. Circulation 118:722-730PubMedCrossRefGoogle Scholar
  60. 60.
    McMurtry MS, Moudgil R, Hashimoto K, Bonnet S, Michelakis ED, Archer SL (2007) Overexpression of human bone morphogenetic protein receptor 2 does not ameliorate monocrotaline pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 292:L872-L878PubMedCrossRefGoogle Scholar
  61. 61.
    Reynolds AM, Xia W, Holmes MD et al (2007) Bone morphogenetic protein type 2 receptor gene therapy attenuates hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 292:L1182-L1192PubMedCrossRefGoogle Scholar
  62. 62.
    Willette RN, Gu JL, Lysko PG, Anderson KM, Minehart H, Yue T (1999) BMP-2 gene expression and effects on human vascular smooth muscle cells. J Vasc Res 36:120-125PubMedCrossRefGoogle Scholar
  63. 63.
    Nakaoka T, Gonda K, Ogita T et al (1997) Inhibition of rat vascular smooth muscle proliferation in vitro and in vivo by bone morphogenetic protein-2. J Clin Invest 100:2824-2832PubMedCrossRefGoogle Scholar
  64. 64.
    Zeisberg M, Hanai Ji, Sugimoto H et al (2003) BMP-7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9:964-968PubMedCrossRefGoogle Scholar
  65. 65.
    Morrissey J, Hruska K, Guo G, Wang S, Chen Q, Klahr S (2002) Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function. J Am Soc Nephrol 13:S14-S21PubMedCrossRefGoogle Scholar
  66. 66.
    Saika S, Ikeda K, Yamanaka O et al (2006) Adenoviral gene transfer of BMP-7, Id2, or Id3 suppresses injury-induced epithelial-to-mesenchymal transition of lens epithelium in mice. Am J Physiol Cell Physiol 290:C282-C289PubMedCrossRefGoogle Scholar
  67. 67.
    Buckley S, Shi W, Driscoll B, Ferrario A, Anderson K, Warburton D (2004) BMP4 signaling induces senescence and modulates the oncogenic phenotype of A549 lung adenocarcinoma cells. Am J Physiol Lung Cell Mol Physiol 286:L81-L86PubMedCrossRefGoogle Scholar
  68. 68.
    Warburton D, Bellusci S (2004) The molecular genetics of lung morphogenesis and injury repair. Paediatr Respir Rev 5:S283-S287PubMedCrossRefGoogle Scholar
  69. 69.
    Long L, Crosby AC, Yang X et al (2009) Altered BMP/TGF-β signaling in rat models of pulmonary hypertension: potential for ALK-5 inhibition in prevention and progression of disease. Circulation (in press)Google Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of MedicineUniversity of Cambridge School of Clinical MedicineCambridgeUK

Personalised recommendations