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Hereditary Haemorrhagic Telangiectasia

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Molecular Basis of Pulmonary Disease

Part of the book series: Respiratory Medicine ((RM))

Abstract

Hereditary Haemorrhagic Telangiectasia (HHT, Osler–Weber–Rendu syndrome) exemplifies diseases which have catalysed advances in the understanding of fundamental pathophysiological mechanisms. The hallmark of HHT is the development of abnormal blood vessels, involving the lung in approximately 50% of cases. This chapter will focus on the molecular mechanisms that underlie their generation. While not all clinical problems in HHT can be directly attributed to the presence of abnormal vessels, the emergent data suggesting non-vascular sequelae of the underlying gene mutations are beyond the scope of this chapter.

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References

  1. Legg W. A case of haemophilia complicated with multiple naevi. Lancet 1876;2:856–7.

    Google Scholar 

  2. Rendu H. Épistaxis répétées chez un sujet porteur de petits angiomes cutanés et muquez. Gazette des Hopitaux (Paris) 1896;135:1322–3.

    Google Scholar 

  3. Rundles RW. Hemorrhagic telangiectasia with pulmonary artery aneurysm: Case report. Am J Med Sci 1945;210:76–81.

    Article  Google Scholar 

  4. Smith JL, Lineback MI. Hereditary hemorrhagic telangiectasia; nine cases in one Negro family, with special reference to hepatic lesions. Am J Med 1954;17:41–9.

    Article  CAS  PubMed  Google Scholar 

  5. Sabbá C, Pasculli G, Suppressa P, D’Ovidio F, Lenato GM, Resta F, Assennato G, Guanti G. Life expectancy in patients with hereditary haemorrhagic telangiectasia. QJM 2006 May;99(5):327–34.

    Article  CAS  PubMed  Google Scholar 

  6. Kjeldsen AD, Vase P, Green A. Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients. J Intern Med 1999;245:31–9.

    Article  CAS  PubMed  Google Scholar 

  7. Bideau A, Brunet G, Heyer E, Plauchu H, Robert JM. An abnormal concentration of cases of Rendu-Osler disease in the Valserine valley of the French Jura: a genealogical and demographic study. Ann Hum Biol 1992;19:233–47.

    Article  CAS  PubMed  Google Scholar 

  8. Jessurun GA, Kamphuis DJ, van der Zande FH, Nossent JC. Cerebral arteriovenous malformations in The Netherlands Antilles. High prevalence of hereditary hemorrhagic telangiectasia-related single and multiple cerebral arteriovenous malformations. Clin Neurol Neurosurg 1993;95:193–8.

    Article  CAS  PubMed  Google Scholar 

  9. Dakeishi M, Shioya T, Wada Y, Shindo T, Otaka K, Manabe M, Nozaki J, Inoue S, Koizumi A. Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan. Hum Mutat 2002;19:140–8.

    Article  CAS  PubMed  Google Scholar 

  10. Shovlin CL, Jackson JE, Bamford KB, Jenkins IH, Benjamin AR, Ramadan H, Kulinskaya E. Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia. Thorax 2008;63:259–66.

    Article  CAS  PubMed  Google Scholar 

  11. Govani FS, Shovlin CL. Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur J Hum Genet 2009;17:860–71.

    Article  CAS  PubMed  Google Scholar 

  12. Abdalla SA, Letarte M. Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet 2006;43:97–110.

    Article  CAS  PubMed  Google Scholar 

  13. Bayrak-Toydemir P, McDonald J, Markewitz B, Lewin S, Miller F, Chou LS, Gedge F, Tang W, Coon H, Mao R. Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations. Am J Med Genet A 2006;140:463–70.

    PubMed  Google Scholar 

  14. Sabba C. A rare and misdiagnosed bleeding disorder: hereditary hemorrhagic telangiectasia. J Thromb Haemost 2005;3:2201–10.

    Article  CAS  PubMed  Google Scholar 

  15. Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, Kjeldsen AD, Plauchu H. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 2000;91:66–7.

    Article  CAS  PubMed  Google Scholar 

  16. Cottin V, Plauchu H, Bayle JY, Barthelet M, Revel D, Cordier JF. Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia. Am J Respir Crit Care Med 2004;169:994–1000.

    Article  PubMed  Google Scholar 

  17. Dutton JA, Jackson JE, Hughes JM, Whyte MK, Peters AM, Ussov W, Allison DJ. Pulmonary arteriovenous malformations: results of treatment with coil embolization in 53 patients. AJR Am J Roentgenol 1995;165:1119–25.

    CAS  PubMed  Google Scholar 

  18. Gupta P, Mordin C, Curtis J, Hughes JM, Shovlin CL, Jackson JE. Pulmonary arteriovenous malformations: effect of embolization on right-to-left shunt, hypoxemia, and exercise tolerance in 66 patients. AJR Am J Roentgenol 2002;179:347–55.

    CAS  PubMed  Google Scholar 

  19. Shovlin CL, Jackson. JE 2010. Pulmonary Arteriovenous malformations and other pulmonary-vascular abnormalities. B. Mason and M. Nadel, eds. Murray and Nadel’s Textbook of Respiratory Medicine. Pennsylvania: Elsevier-Saunders.

    Google Scholar 

  20. Shovlin CL, Sodhi V, McCarthy A, Lasjaunias P, Jackson JE, Sheppard MN. Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): suggested approach for obstetric services. BJOG 2008;115:1108–15.

    Article  CAS  PubMed  Google Scholar 

  21. Post MC, van Gent MW, Snijder RJ, Mager JJ, Schonewille WJ, Plokker HW, Westermann CJ. Pulmonary arteriovenous malformations and migraine: a new vision. Respiration 2008;76:228–33.

    Article  CAS  PubMed  Google Scholar 

  22. Shovlin CL, Tighe HC, Davies RJ, Gibbs JS, Jackson JE. Embolisation of pulmonary arteriovenous malformations: no consistent effect on pulmonary artery pressure. Eur Respir J 2008;32:162–9.

    Article  CAS  PubMed  Google Scholar 

  23. Olivieri C, Lanzarini L, Pagella F, Semino L, Corno S, Valacca C, Plauchu H, Lesca G, Barthelet M, Buscarini E, et al. Echocardiographic screening discloses increased values of pulmonary artery systolic pressure in 9 of 68 unselected patients affected with hereditary hemorrhagic telangiectasia. Genet Med 2006;8:183–90.

    Article  PubMed  Google Scholar 

  24. Trembath RC, Thomson JR, Machado RD, Morgan NV, Atkinson C, Winship I, Simonneau G, Galie N, Loyd JE, Humbert M, et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2001;345:325–34.

    Article  CAS  PubMed  Google Scholar 

  25. Haitjema T, ten Berg JM, Overtoom TT, Ernst JM, Westermann CJ. Unusual complications after embolization of a pulmonary arteriovenous malformation. Chest 1996;109:1401–4.

    Article  CAS  PubMed  Google Scholar 

  26. Plauchu H, de Chadarevian JP, Bideau A, Robert JM. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet 1989;32:291–7.

    Article  CAS  PubMed  Google Scholar 

  27. Porteous ME, Burn J, Proctor SJ. Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet 1992;29:527–30.

    Article  CAS  PubMed  Google Scholar 

  28. Shovlin CL, Hughes JM, Tuddenham EG, Temperley I, Perembelon YF, Scott J, Seidman CE, Seidman JG. A gene for hereditary haemorrhagic telangiectasia maps to chromosome 9q3. Nat Genet 1994;6:205–9.

    Article  CAS  PubMed  Google Scholar 

  29. Hanes FM. Multiple hereditary telangiectases causing hemorrhage (Hereditary Hemorrhagic Telangiectasia). Bull Johns Hopkins 1909;20:63–73.

    Google Scholar 

  30. Hales MR. Multiple small arteriovenous fistulae of the lungs. Am J Pathol 1956;32:927–43.

    CAS  PubMed  Google Scholar 

  31. Yater WM, Finnegan J,, Giffin HM. Pulmonary arteriovenous fistula; review of the literature and report of two cases. J Am Med Assoc 1949;141:581–9.

    CAS  PubMed  Google Scholar 

  32. Bourdeau A, Cymerman U, Paquet ME, Meschino W, McKinnon WC, Guttmacher AE, Becker L, Letarte M. Endoglin expression is reduced in normal vessels but still detectable in arteriovenous malformations of patients with hereditary hemorrhagic telangiectasia type 1. Am J Pathol 2000;156:911–23.

    CAS  PubMed  Google Scholar 

  33. Shovlin CL, Scott J. Inherited diseases of the vasculature. Annu Rev Physiol 1996;58:483–507.

    Article  CAS  PubMed  Google Scholar 

  34. Braverman IM, Keh A, Jacobson BS. Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia. J Invest Dermatol 1990;95:422–7.

    Article  CAS  PubMed  Google Scholar 

  35. Braverman IM, Ken-Yen A. Ultrastructure and three-dimensional reconstruction of several macular and papular telangiectases. J Invest Dermatol 1983;81:489–97.

    Article  CAS  PubMed  Google Scholar 

  36. Shovlin CL, Sulaiman NL, Govani FS, Jackson JE, Begbie ME. Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): association with venous thromboembolism. Thromb Haemost 2007;98:1031–9.

    CAS  PubMed  Google Scholar 

  37. Cirulli A, Loria MP, Dambra P, Di Serio F, Ventura MT, Amati L, Jirillo E, Sabba C. Patients with Hereditary Hemorrhagic Telangectasia (HHT) exhibit a deficit of polymorphonuclear cell and monocyte oxidative burst and phagocytosis: a possible correlation with altered adaptive immune responsiveness in HHT. Curr Pharm Des 2006;12:1209–15.

    Article  CAS  PubMed  Google Scholar 

  38. Jacobson BS. Hereditary hemorrhagic telangiectasia: A model for blood vessel growth and enlargement. Am J Pathol 2000;156:737–42.

    CAS  PubMed  Google Scholar 

  39. Higgins CB, Wexler L. Clinical and angiographic features of pulmonary arteriovenous fistulas in children. Radiology 1976;119:171–5.

    CAS  PubMed  Google Scholar 

  40. Muller JY, Michailov T, Izrael V, Bernard J. [Hereditary haemorrhagic telangiectasia in a large Saharan family. 87 cases in the same family (author’s transl)]. Nouv Presse Med 1978;7:1723–5.

    CAS  PubMed  Google Scholar 

  41. Snyder LH, Doan. CA. Clinical and experimental studies in human inheritance- Is the homozygous form of multiple telangiectasia lethal?. J Lab Clin Med 1944;29:1211–6.

    Google Scholar 

  42. Elharith E, Kuhnau W, Schmidtke J, Gadzicki D, Ahmed M, Krawczak M, Stuhrmann M. Hereditary hemorrhagic telangiectasia is caused by the Q490X mutation of the ACVRL1 gene in a large Arab family: support of homozygous lethality. Eur J Med Genet 2006;49:323–30.

    Article  Google Scholar 

  43. Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, Mitchell G, Drouin E, Westermann CJ, Marchuk DA. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 2004;363:852–9.

    Article  CAS  PubMed  Google Scholar 

  44. McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J, 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.

    Article  CAS  PubMed  Google Scholar 

  45. Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ, Stenzel TT, Speer M, Pericak-Vance MA, Diamond A, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996;13:189–95.

    Article  CAS  PubMed  Google Scholar 

  46. Cole SG, Begbie ME, Wallace GM, Shovlin CL. A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5. J Med Genet 2005;42:577–82.

    Article  CAS  PubMed  Google Scholar 

  47. Bayrak-Toydemir P, McDonald J, Akarsu N, Toydemir RM, Calderon F, Tuncali T, Tang W, Miller F, Mao R. A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7. Am J Med Genet A 2006;140:2155–62.

    PubMed  Google Scholar 

  48. Shovlin CL, Hughes JM, Scott J, Seidman CE, Seidman JG. Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia. Am J Hum Genet 1997;61:68–79.

    Article  CAS  PubMed  Google Scholar 

  49. Pece-Barbara N, Cymerman U, Vera S, Marchuk DA, Letarte M. Expression analysis of four endoglin missense mutations suggests that haploinsufficiency is the predominant mechanism for hereditary hemorrhagic telangiectasia type 1. Hum Mol Genet 1999;8:2171–81.

    Article  CAS  PubMed  Google Scholar 

  50. Pece N, Vera S, Cymerman U, White RI Jr., Wrana JL, Letarte M. Mutant endoglin in hereditary hemorrhagic telangiectasia type 1 is transiently expressed intracellularly and is not a dominant negative. J Clin Invest 1997;100:2568–79.

    Article  CAS  PubMed  Google Scholar 

  51. Cymerman U, Vera S, Pece-Barbara N, Bourdeau A, White RI Jr., Dunn J, Letarte M. Identification of hereditary hemorrhagic telangiectasia type 1 in newborns by protein expression and mutation analysis of endoglin. Pediatr Res 2000;47:24–35.

    Article  CAS  PubMed  Google Scholar 

  52. Paquet ME, Pece-Barbara N, Vera S, Cymerman U, Karabegovic A, Shovlin C, Letarte M. Analysis of several endoglin mutants reveals no endogenous mature or secreted protein capable of interfering with normal endoglin function. Hum Mol Genet 2001;10:1347–57.

    Article  CAS  PubMed  Google Scholar 

  53. Cymerman U, Vera S, Karabegovic A, Abdalla S, Letarte M. Characterization of 17 novel endoglin mutations associated with hereditary hemorrhagic telangiectasia. Hum Mutat 2003;21:482–92.

    Article  CAS  PubMed  Google Scholar 

  54. Lux A, Gallione CJ, Marchuk DA. Expression analysis of endoglin missense and truncation mutations: insights into protein structure and disease mechanisms. Hum Mol Genet 2000;9:745–55.

    Article  CAS  PubMed  Google Scholar 

  55. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2006;12:642–9.

    Article  CAS  PubMed  Google Scholar 

  56. Knudson AG Jr. Hereditary cancer, oncogenes, and antioncogenes. Cancer Res 1985;45:1437–43.

    CAS  PubMed  Google Scholar 

  57. Harrison RE, Flanagan JA, Sankelo M, Abdalla SA, Rowell J, Machado RD, Elliott CG, Robbins IM, Olschewski H, McLaughlin V, 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.

    Article  CAS  PubMed  Google Scholar 

  58. Chaouat A, Coulet F, Favre C, Simonneau G, Weitzenblum E, Soubrier F, Humbert M. Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. Thorax 2004;59:446–8.

    Article  CAS  PubMed  Google Scholar 

  59. Aretz S, Stienen D, Uhlhaas S, Stolte M, Entius MM, Loff S, Back W, Kaufmann A, Keller KM, Blaas SH, et al. High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet 2007;44:702–9.

    Article  CAS  PubMed  Google Scholar 

  60. Sabba C, Pasculli G, Lenato GM, Suppressa P, Lastella P, Memeo M, Dicuonzo F, Guant G. Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers. J Thromb Haemost 2007;5:1149–57.

    Article  CAS  PubMed  Google Scholar 

  61. Lesca G, Olivieri C, Burnichon N, Pagella F, Carette MF, Gilbert-Dussardier B, Goizet C, Roume J, Rabilloud M, Saurin JC, et al. Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network. Genet Med 2007;9:14–22.

    Article  PubMed  Google Scholar 

  62. Bossler AD, Richards J, George C, Godmilow L, Ganguly A. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum Mutat 2006;27:667–75.

    Article  CAS  PubMed  Google Scholar 

  63. Letteboer TG, Mager JJ, Snijder RJ, Koeleman BP, Lindhout D, Ploosvan Amstel JK, Westermann CJ. Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia. J Med Genet 2006;43:371–7.

    Article  CAS  PubMed  Google Scholar 

  64. Kjeldsen AD, Moller TR, Brusgaard K, Vase P, Andersen PE. Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia. J Intern Med 2005;258:349–55.

    Article  CAS  PubMed  Google Scholar 

  65. Berg J, Porteous M, Reinhardt D, Gallione C, Holloway S, Umasunthar T, Lux A, McKinnon W, Marchuk D, Guttmacher A. Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations. J Med Genet 2003;40:585–90.

    Article  CAS  PubMed  Google Scholar 

  66. Chang H, Brown CW, Matzuk MM. Genetic analysis of the mammalian transforming growth factor-beta superfamily. Endocr Rev 2002;23:787–823.

    Article  CAS  PubMed  Google Scholar 

  67. ten Dijke P, Goumans MJ, Pardali E. Endoglin in angiogenesis and vascular diseases. Angiogenesis 2008.

    Google Scholar 

  68. Lebrin F, Mummery CL. Endoglin-mediated vascular remodeling: mechanisms underlying hereditary hemorrhagic telangiectasia. Trends Cardiovasc Med 2008;18:25–32.

    Article  CAS  PubMed  Google Scholar 

  69. Cheifetz S, Bellon T, Cales C, Vera S, Bernabeu C, Massague J, Letarte M. Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells. J Biol Chem 1992;267:19027–30.

    CAS  PubMed  Google Scholar 

  70. St Jacques S, Forte M, Lye SJ, Letarte M. Localization of endoglin, a transforming growth factor-beta binding protein, and of CD44 and integrins in placenta during the first trimester of pregnancy. Biol Reprod 1994;51:405–13.

    Article  CAS  PubMed  Google Scholar 

  71. Arthur HM, Ure J, Smith AJ, Renforth G, Wilson DI, Torsney E, Charlton R, Parums DV, Jowett T, Marchuk DA, et al. Endoglin, an ancillary TGFbeta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development. Dev Biol 2000;217:42–53.

    Article  CAS  PubMed  Google Scholar 

  72. Yamashita H, Ichijo H, Grimsby S, Moren A, ten Dijke P, Miyazono K. Endoglin forms a heteromeric complex with the signaling receptors for transforming growth factor-beta. J Biol Chem 1994;269:1995–2001.

    CAS  PubMed  Google Scholar 

  73. Barbara NP, Wrana JL, Letarte M. Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily. J Biol Chem 1999;274:584–94.

    Article  CAS  PubMed  Google Scholar 

  74. Scharpfenecker M, van Dinther M, Liu Z, van Bezooijen RL, Zhao Q, Pukac L, Lowik CW, ten Dijke P. BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. J Cell Sci 2007;120:964–72.

    Article  CAS  PubMed  Google Scholar 

  75. David L, Mallet C, Mazerbourg S, Feige JJ, Bailly S. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood 2007;109:1953–61.

    Article  CAS  PubMed  Google Scholar 

  76. Lastres P, Letamendia A, Zhang H, Rius C, Almendro N, Raab U, Lopez LA, Langa C, Fabra A, Letarte M, et al. Endoglin modulates cellular responses to TGF-beta 1. J Cell Biol 1996;133:1109–21.

    Article  CAS  PubMed  Google Scholar 

  77. Lebrin F, Goumans MJ, Jonker L, Carvalho RL, Valdimarsdottir G, Thorikay M, Mummery C, Arthur HM, ten Dijke P. Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction. EMBO J 2004;23:4018–28.

    Article  CAS  PubMed  Google Scholar 

  78. Pece-Barbara N, Vera S, Kathirkamathamby K, Liebner S, Di Guglielmo GM, Dejana E, Wrana JL, Letarte M. Endoglin null endothelial cells proliferate faster and are more responsive to transforming growth factor beta1 with higher affinity receptors and an activated Alk1 pathway. J Biol Chem 2005;280:27800–8.

    Article  CAS  PubMed  Google Scholar 

  79. Perez-Gomez E, Eleno N, Lopez-Novoa JM, Ramirez JR, Velasco B, Letarte M, Bernabeu C, Quintanilla M. Characterization of murine S-endoglin isoform and its effects on tumor development. Oncogene 2005;24:4450–61.

    Article  CAS  PubMed  Google Scholar 

  80. Velasco S, Alvarez-Munoz P, Pericacho M, ten Dijke P, Bernabeu C, Lopez-Novoa JM, Rodriguez-Barbero A. 2008. L- and S-endoglin differentially modulate TGF{beta}1 signaling mediated by ALK1 and ALK5 in L6E9 myoblasts. J Cell Sci.

    Google Scholar 

  81. Sanz-Rodriguez F, Guerrero-Esteo M, Botella LM, Banville D, Vary CP, Bernabeu C. Endoglin regulates cytoskeletal organization through binding to ZRP-1, a member of the Lim family of proteins. J Biol Chem 2004;279:32858–68.

    Article  CAS  PubMed  Google Scholar 

  82. Piek E, Heldin CH, ten Dijke P. Specificity, diversity, and regulation in TGF-beta superfamily signaling. FASEB J 1999;13:2105–24.

    CAS  PubMed  Google Scholar 

  83. Lee SJ, McPherron AC. Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci U S A 2001;98:9306–11.

    Article  CAS  PubMed  Google Scholar 

  84. Yeo C, Whitman M. Nodal signals to Smads through Cripto-dependent and Cripto-independent mechanisms. Mol Cell 2001;7:949–57.

    Article  CAS  PubMed  Google Scholar 

  85. Oh SP, Yeo CY, Lee Y, Schrewe H, Whitman M, Li E. Activin type IIA and IIB receptors mediate Gdf11 signaling in axial vertebral patterning. Genes Dev 2002;16:2749–54.

    Article  CAS  PubMed  Google Scholar 

  86. Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003;113:685–700.

    Article  CAS  PubMed  Google Scholar 

  87. ten Dijke P, Yamashita H, Ichijo H, Franzen P, Laiho M, Miyazono K, Heldin CH. Characterization of type I receptors for transforming growth factor-beta and activin. Science 1994;264:101–4.

    Article  CAS  PubMed  Google Scholar 

  88. ten Dijke P, Ichijo H, Franzen P, Schulz P, Saras J, Toyoshima H, Heldin CH, Miyazono K. Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity. Oncogene 1993;8:2879–87.

    CAS  PubMed  Google Scholar 

  89. Alejandre-Alcazar MA, Michiels-Corsten M, Vicencio AG, Reiss I, Ryu J, de Krijger RR, Haddad GG, Tibboel D, Seeger W, Eickelberg O, et al. TGF-beta signaling is dynamically regulated during the alveolarization of rodent and human lungs. Dev Dyn 2008;237:259–69.

    Article  CAS  PubMed  Google Scholar 

  90. Seki T, Yun J, Oh SP. Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling. Circ Res 2003;93:682–9.

    Article  CAS  PubMed  Google Scholar 

  91. Hong KH, Seki T, Oh SP. Activin receptor-like kinase 1 is essential for placental vascular development in mice. Lab Invest 2007;87:670–9.

    Article  CAS  PubMed  Google Scholar 

  92. Lux A, Attisano L, Marchuk DA. Assignment of transforming growth factor beta1 and beta3 and a third new ligand to the type I receptor ALK-1. J Biol Chem 1999;274:9984–92.

    Article  CAS  PubMed  Google Scholar 

  93. Chen YG, Massague J. Smad1 recognition and activation by the ALK1 group of transforming growth factor-beta family receptors. J Biol Chem 1999;274:3672–7.

    Article  CAS  PubMed  Google Scholar 

  94. Oh SP, Seki T, Goss KA, Imamura T, Yi Y, Donahoe PK, Li L, Miyazono K, ten Dijke P, Kim S, et al. Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A 2000;97:2626–31.

    Article  CAS  PubMed  Google Scholar 

  95. Goumans MJ, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, ten Dijke P. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J 2002;21:1743–53.

    Article  CAS  PubMed  Google Scholar 

  96. Goumans MJ, Valdimarsdottir G, Itoh S, Lebrin F, Larsson J, Mummery C, Karlsson S, ten Dijke P. Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. Mol Cell 2003;12:817–28.

    Article  CAS  PubMed  Google Scholar 

  97. Lamouille S, Mallet C, Feige JJ, Bailly S. Activin receptor-like kinase 1 is implicated in the maturation phase of angiogenesis. Blood 2002;100:4495–501.

    Article  CAS  PubMed  Google Scholar 

  98. Park SO, Lee YJ, Seki T, Hong KH, Fliess N, Jiang Z, Park A, Wu X, Kaartinen V, Roman BL, et al. ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2 (HHT2). Blood 2008;111:633–42.

    Article  CAS  PubMed  Google Scholar 

  99. Brown MA, Zhao Q, Baker KA, Naik C, Chen C, Pukac L, Singh M, Tsareva T, Parice Y, Mahoney A, et al. Crystal structure of BMP-9 and functional interactions with pro-region and receptors. J Biol Chem 2005;280:25111–8.

    Article  CAS  PubMed  Google Scholar 

  100. Bourdeau A, Dumont DJ, Letarte M. A murine model of hereditary hemorrhagic telangiectasia. J Clin Invest 1999;104:1343–51.

    Article  CAS  PubMed  Google Scholar 

  101. Li DY, Sorensen LK, Brooke BS, Urness LD, Davis EC, Taylor DG, Boak BB, Wendel DP. Defective angiogenesis in mice lacking endoglin. Science 1999;284:1534–7.

    Article  CAS  PubMed  Google Scholar 

  102. Urness LD, Sorensen LK, Li DY. Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet 2000;26:328–31.

    Article  CAS  PubMed  Google Scholar 

  103. Adams RH, Porras A, Alonso G, Jones M, Vintersten K, Panelli S, Valladares A, Perez L, Klein R, Nebreda AR. Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development. Mol Cell 2000;6:109–16.

    Article  CAS  PubMed  Google Scholar 

  104. Satomi J, Mount RJ, Toporsian M, Paterson AD, Wallace MC, Harrison RV, Letarte M. Cerebral vascular abnormalities in a murine model of hereditary hemorrhagic telangiectasia. Stroke 2003;34:783–9.

    Article  PubMed  Google Scholar 

  105. Torsney E, Charlton R, Diamond AG, Burn J, Soames JV, Arthur HM. Mouse model for hereditary hemorrhagic telangiectasia has a generalized vascular abnormality. Circulation 2003;107:1653–7.

    Article  PubMed  Google Scholar 

  106. Srinivasan S, Hanes MA, Dickens T, Porteous ME, Oh SP, Hale LP, Marchuk DA. A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2. Hum Mol Genet 2003;12:473–82.

    Article  CAS  PubMed  Google Scholar 

  107. Park SO, Lee YJ, Seki T, Hong KH, Fliess N, Jiang Z, Park A, Wu X, Kaartinen V, Roman BL, et al. ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2 (HHT2). Blood 2007.

    Google Scholar 

  108. Yang X, Li C, Herrera PL, Deng CX. Generation of Smad4/Dpc4 conditional knockout mice. Genesis 2002;32:80–1.

    Article  CAS  PubMed  Google Scholar 

  109. Allinson KR, Carvalho RL, Vanden BS, Mummery CL, Arthur HM. Generation of a floxed allele of the mouse Endoglin gene. Genesis 2007;45:391–5.

    Article  CAS  PubMed  Google Scholar 

  110. Adams RH, Alitalo K. Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 2007;8:464–78.

    Article  CAS  PubMed  Google Scholar 

  111. Carmeliet P. Angiogenesis in life, disease and medicine. Nature 2005;438:932–6.

    Article  CAS  PubMed  Google Scholar 

  112. Pepper MS. Transforming growth factor-beta: vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev 1997;8:21–43.

    Article  CAS  PubMed  Google Scholar 

  113. Mallet C, Vittet D, Feige JJ, Bailly S. TGFbeta1 induces vasculogenesis and inhibits angiogenic sprouting in an embryonic stem cell differentiation model: respective contribution of ALK1 and ALK5. Stem Cells 2006;24:2420–7.

    Article  CAS  PubMed  Google Scholar 

  114. Jerkic M, Rivas-Elena JV, Santibanez JF, Prieto M, Rodriguez-Barbero A, Perez-Barriocanal F, Pericacho M, Arevalo M, Vary CP, Letarte M, et al. Endoglin regulates cyclooxygenase-2 expression and activity. Circ Res 2006;99:248–56.

    Article  CAS  PubMed  Google Scholar 

  115. Roman BL, Pham VN, Lawson ND, Kulik M, Childs S, Lekven AC, Garrity DM, Moon RT, Fishman MC, Lechleider RJ, et al. Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels. Development 2002;129:3009–19.

    CAS  PubMed  Google Scholar 

  116. Cirulli A, Liso A, D‘Ovidio F, Mestice A, Pasculli G, Gallitelli M, Rizzi R, Specchia G, Sabba C. Vascular endothelial growth factor serum levels are elevated in patients with hereditary hemorrhagic telangiectasia. Acta Haematol 2003;110:29–32.

    Article  CAS  PubMed  Google Scholar 

  117. Sadick H, Riedel F, Naim R, Goessler U, Hormann K, Hafner M, Lux A. Patients with hereditary hemorrhagic telangiectasia have increased plasma levels of vascular endothelial growth factor and transforming growth factor-beta1 as well as high ALK1 tissue expression. Haematologica 2005;90:818–28.

    CAS  PubMed  Google Scholar 

  118. Xu B, Wu YQ, Huey M, Arthur HM, Marchuk DA, Hashimoto T, Young WL, Yang GY. Vascular endothelial growth factor induces abnormal microvasculature in the endoglin heterozygous mouse brain. J Cereb Blood Flow Metab 2004;24:237–44.

    Article  CAS  PubMed  Google Scholar 

  119. Mitchell A, Adams LA, MacQuillan G, Tibballs J, Vanden Driesen R, Delriviere L. Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasia. Liver Transpl 2008;14:210–3.

    Article  PubMed  Google Scholar 

  120. Gale NW, Yancopoulos GD. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev 1999;13:1055–66.

    Article  CAS  PubMed  Google Scholar 

  121. Wang HU, Chen ZF, Anderson DJ. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 1998;93:741–53.

    Article  CAS  PubMed  Google Scholar 

  122. Shutter JR, Scully S, Fan W, Richards WG, Kitajewski J, Deblandre GA, Kintner CR, Stark KL. Dll4, a novel Notch ligand expressed in arterial endothelium. Genes Dev 2000;14:1313–8.

    CAS  PubMed  Google Scholar 

  123. Zhong TP, Rosenberg M, Mohideen MA, Weinstein B, Fishman MC. gridlock, an HLH gene required for assembly of the aorta in zebrafish. Science 2000;287:1820–4.

    Article  CAS  PubMed  Google Scholar 

  124. Zhong TP, Childs S, Leu JP, Fishman MC. Gridlock signalling pathway fashions the first embryonic artery. Nature 2001;414:216–20.

    Article  CAS  PubMed  Google Scholar 

  125. Gridley T. Vascular biology: vessel guidance. Nature 2007;445:722–3.

    Article  CAS  PubMed  Google Scholar 

  126. Krebs LT, Shutter JR, Tanigaki K, Honjo T, Stark KL, Gridley T. Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev 2004;18:2469–73.

    Article  CAS  PubMed  Google Scholar 

  127. Carlson TR, Yan Y, Wu X, Lam MT, Tang GL, Beverly LJ, Messina LM, Capobianco AJ, Werb Z, Wang R. Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Proc Natl Acad Sci U S A 2005;102:9884–9.

    Article  CAS  PubMed  Google Scholar 

  128. Iso T, Maeno T, Oike Y, Yamazaki M, Doi H, Arai M, Kurabayashi M. Dll4-selective Notch signaling induces ephrinB2 gene expression in endothelial cells. Biochem Biophys Res Commun 2006;341:708–14.

    Article  CAS  PubMed  Google Scholar 

  129. Jerkic M, Rivas-Elena JV, Prieto M, Carron R, Sanz-Rodriguez F, Perez-Barriocanal F, Rodriguez-Barbero A, Bernabeu C, Lopez-Novoa JM. Endoglin regulates nitric oxide-dependent vasodilatation. FASEB J 2004;18:609–11.

    CAS  PubMed  Google Scholar 

  130. Toporsian M, Gros R, Kabir MG, Vera S, Govindaraju K, Eidelman DH, Husain M, Letarte M. A role for endoglin in coupling eNOS activity and regulating vascular tone revealed in hereditary hemorrhagic telangiectasia. Circ Res 2005;96:684–92.

    Article  CAS  PubMed  Google Scholar 

  131. Fernandez L, Garrido-Martin EM, Sanz-Rodriguez F, Pericacho M, Rodriguez-Barbero A, Eleno N, Lopez-Novoa JM, Duwell A, Vega MA, Bernabeu C, et al. Gene expression fingerprinting for human hereditary hemorrhagic telangiectasia. Hum Mol Genet 2007;16:1515–33.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Respiratory Medicine, Imperial College London, London, UK

    Claire Shovlin PhD, MA, FRCP

  2. Department of Physiology and Functional Genomics, University of Florida Cancer and Genetic Research Complex, Gainesville, FL, USA

    S. Paul Oh PhD

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  1. Claire Shovlin PhD, MA, FRCP
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  2. S. Paul Oh PhD
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  1. Div. Pulmonary & Critical Care, University of Cincinnati, Albert Sabin Way 231, Cincinnati, 45267, USA

    Francis X. McCormack

  2. Div. Pulmonary & Critical Care, University of Cincinnati, Albert Sabin Way 231, Cincinnati, 45267, USA

    Ralph J. Panos

  3. Medical Center, Cincinnati Children's Hospital, Burnet Ave. 3333, Cincinnati, 45229, USA

    Bruce C. Trapnell

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Shovlin, C., Paul Oh, S. (2010). Hereditary Haemorrhagic Telangiectasia. In: McCormack, F., Panos, R., Trapnell, B. (eds) Molecular Basis of Pulmonary Disease. Respiratory Medicine. Humana Press. https://doi.org/10.1007/978-1-59745-384-4_7

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