Connective Tissue Disorders and Cardiovascular Complications: The Indomitable Role of Transforming Growth Factor-Beta Signaling

  • Jason B. Wheeler
  • John S. Ikonomidis
  • Jeffrey A. JonesEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 802)


Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that cosegregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic root dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. Given the evidence of increased transforming growth factor-beta (TGF-β) signaling in MFS and LDS, this signaling pathway may represent the common link in this relationship. To further explore this hypothetical link, this chapter will review the TGF-β signaling pathway, heritable connective tissue syndromes related to TGF-β receptor (TGFBR) mutations, and discuss the pathogenic contribution of TGF-β to these syndromes with a primary focus on the cardiovascular system.


Shprintzen-Goldberg syndrome, hereditary hemorrhagic telangiectasia (HHT) Marfan syndrome (MFS) Loeys-Dietz syndrome (LDS) Primary pulmonary hypertension Fibrodysplasia ossificans progressiva (FOP) Familial thoracic aortic aneurysm and dissection syndrome (FTAAD) Smad TGF-β receptor Curacao diagnostic criteria 



Aortic Aneurysm Thoracic


Angiotensin Converting Enzyme


Activin Receptor-like Kinase 1


Activin Receptor-like Kinase 3


Activin Receptor-like Kinase 5


Aneurysm-Osteoarthritis Syndrome


Angiotensin II Receptor Type I


Angiotensin II Receptor Type II


Arterial Tortuosity Syndrome


Arteriovenous Malformation


Bicuspid Aortic Valve


Bone Morphogenetic Protein


Bone Morphogenetic Protein Receptor 1A


Bone Morphogenetic Protein Receptor 2


Common Smad


Connective Tissue Growth Factor


Extracellular Matrix


Extracellular Signal-Regulated Kinase 1/2


Endovascular Aortic Repair




Fibrodysplasia Ossificans Progressiva


Familial Thoracic Aortic Aneurysm and Dissection Syndrome




Hereditary Hemorrhagic Telangiectasia, Type 1


Hereditary Hemorrhagic Telangiectasia, Type 2


c-Jun N-terminal Kinase


Latent Associated Protein


Loeys-Dietz Syndrome


Large Latent Complex


Latent Transforming Growth Factor-Beta Binding Protein


Mitogen-Activated Protein Kinase


Marfan Syndrome


Matrix Metalloproteinases


Mitral Valve Prolapse


Online Mendelian Inheritance in Man


Pulmonary Artery Hypertension


Patent Ductus Arteriosus


Phosphoinositide 3-Kinase


Rheumatoid Arthritis


Receptor Smad


Smad Anchor for Receptor Activation


Shprintzen-Goldberg Syndrome


Solute Carrier Family 2, Facilitated Glucose Transporter Member 10


Systemic Lupus Erythematosus


Smad Ubiquitination Regulatory Factor


Thoracic Aortic Aneurysm


Transforming Growth Factor-Beta Associated Kinase 1


Transcription Factors


Transforming Growth Factor-Beta


Transforming Growth Factor-Beta Receptor, Type-I


Transforming Growth Factor-Beta Receptor, Type-II


Tissue Inhibitors of Matrix Metalloproteinases


Tumor Necrosis Factor Receptor Associated Factor 6


  1. 1.
    Judge DP, Dietz HC (2005) Marfan’s syndrome. Lancet 366(9501):1965–1976PubMedCentralPubMedGoogle Scholar
  2. 2.
    Dietz HC (1993) Marfan syndrome. In: Pagon RA (ed) Gene reviews. University of Washington, SeattleGoogle Scholar
  3. 3.
    Unsold C et al (2001) Latent TGF-beta binding protein LTBP-1 contains three potential extracellular matrix interacting domains. J Cell Sci 114(Pt 1):187–197PubMedGoogle Scholar
  4. 4.
    Taipale J et al (1996) Latent transforming growth factor-beta 1 and its binding protein are components of extracellular matrix microfibrils. J Histochem Cytochem 44(8):875–889PubMedGoogle Scholar
  5. 5.
    Dallas SL et al (1995) Dual role for the latent transforming growth factor-beta binding protein in storage of latent TGF-beta in the extracellular matrix and as a structural matrix protein. J Cell Biol 131(2):539–549PubMedGoogle Scholar
  6. 6.
    Isogai Z et al (2003) Latent transforming growth factor beta-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J Biol Chem 278(4):2750–2757PubMedGoogle Scholar
  7. 7.
    Neptune ER et al (2003) Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 33(3):407–411PubMedGoogle Scholar
  8. 8.
    Loeys BL et al (2005) A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 37(3):275–281PubMedGoogle Scholar
  9. 9.
    Wrana JL et al (1992) TGF beta signals through a heteromeric protein kinase receptor complex. Cell 71(6):1003–1014PubMedGoogle Scholar
  10. 10.
    Ramirez F, Rifkin DB (2003) Cell signaling events: a view from the matrix. Matrix Biol 22(2):101–107PubMedGoogle Scholar
  11. 11.
    Hynes RO (2009) The extracellular matrix: not just pretty fibrils. Science 326(5957):1216–1219PubMedCentralPubMedGoogle Scholar
  12. 12.
    Brekken RA, Sage EH (2001) SPARC, a matricellular protein: at the crossroads of cell-matrix communication. Matrix Biol 19(8):816–827PubMedGoogle Scholar
  13. 13.
    Annes JP, Munger JS, Rifkin DB (2003) Making sense of latent TGFbeta activation. J Cell Sci 116(Pt 2):217–224PubMedGoogle Scholar
  14. 14.
    Wrana JL et al (1994) Mechanism of activation of the TGF-beta receptor. Nature 370(6488):341–347PubMedGoogle Scholar
  15. 15.
    Moustakas A, Souchelnytskyi S, Heldin CH (2001) Smad regulation in TGF-beta signal transduction. J Cell Sci 114(Pt 24):4359–4369PubMedGoogle Scholar
  16. 16.
    Feng XH, Derynck R (2005) Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol 21:659–693PubMedGoogle Scholar
  17. 17.
    Park SH (2005) Fine tuning and cross-talking of TGF-beta signal by inhibitory Smads. J Biochem Mol Biol 38(1):9–16PubMedGoogle Scholar
  18. 18.
    Imamura T et al (1997) Smad6 inhibits signalling by the TGF-beta superfamily. Nature 389(6651):622–626PubMedGoogle Scholar
  19. 19.
    Hata A et al (1998) Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev 12(2):186–197PubMedGoogle Scholar
  20. 20.
    Wicks SJ et al (2006) Reversible ubiquitination regulates the Smad/TGF-beta signalling pathway. Biochem Soc Trans 34(Pt 5):761–763PubMedGoogle Scholar
  21. 21.
    Ebisawa T et al (2001) Smurf1 interacts with transforming growth factor-beta type-I receptor through Smad7 and induces receptor degradation. J Biol Chem 276(16):12477–12480PubMedGoogle Scholar
  22. 22.
    Kavsak P et al (2000) Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell 6(6):1365–1375PubMedGoogle Scholar
  23. 23.
    Droguett R et al (2006) Extracellular proteoglycans modify TGF-beta bio-availability attenuating its signaling during skeletal muscle differentiation. Matrix Biol 25(6):332–341PubMedGoogle Scholar
  24. 24.
    Stander M et al (1999) Transforming growth factor-beta and p-21: multiple molecular targets of decorin-mediated suppression of neoplastic growth. Cell Tissue Res 296(2):221–227PubMedGoogle Scholar
  25. 25.
    Lopez-Casillas F et al (1994) Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors: mapping of ligand binding and GAG attachment sites. J Cell Biol 124(4):557–568PubMedGoogle Scholar
  26. 26.
    Yu L, Hebert MC, Zhang YE (2002) TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. EMBO J 21(14):3749–3759PubMedGoogle Scholar
  27. 27.
    Dumont N, Bakin AV, Arteaga CL (2003) Autocrine transforming growth factor-beta signaling mediates Smad-independent motility in human cancer cells. J Biol Chem 278(5):3275–3285PubMedGoogle Scholar
  28. 28.
    Griswold-Prenner I et al (1998) Physical and functional interactions between type-I transforming growth factor beta receptors and Balpha, a WD-40 repeat subunit of phosphatase 2A. Mol Cell Biol 18(11):6595–6604PubMedCentralPubMedGoogle Scholar
  29. 29.
    Itoh S et al (2003) Elucidation of Smad requirement in transforming growth factor-beta type-I receptor-induced responses. J Biol Chem 278(6):3751–3761PubMedGoogle Scholar
  30. 30.
    Wilkes MC et al (2003) Cell-type-specific activation of PAK2 by transforming growth factor beta independent of Smad2 and Smad3. Mol Cell Biol 23(23):8878–8889PubMedCentralPubMedGoogle Scholar
  31. 31.
    Choy L, Derynck R (1998) The type-II transforming growth factor (TGF)-beta receptor-interacting protein TRIP-1 acts as a modulator of the TGF-beta response. J Biol Chem 273(47):31455–31462PubMedGoogle Scholar
  32. 32.
    Ozdamar B et al (2005) Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 307(5715):1603–1609PubMedGoogle Scholar
  33. 33.
    Hocevar BA, Brown TL, Howe PH (1999) TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. EMBO J 18(5):1345–1356PubMedGoogle Scholar
  34. 34.
    Imamichi Y et al (2005) TGF beta-induced focal complex formation in epithelial cells is mediated by activated ERK and JNK MAP kinases and is independent of Smad4. Biol Chem 386(3):225–236PubMedGoogle Scholar
  35. 35.
    Remy I, Montmarquette A, Michnick SW (2004) PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3. Nat Cell Biol 6(4):358–365PubMedGoogle Scholar
  36. 36.
    Runyan CE, Schnaper HW, Poncelet AC (2004) The phosphatidylinositol 3-kinase/Akt pathway enhances Smad3-stimulated mesangial cell collagen I expression in response to transforming growth factor-beta1. J Biol Chem 279(4):2632–2639PubMedGoogle Scholar
  37. 37.
    Yakymovych I et al (2001) Regulation of Smad signaling by protein kinase C. FASEB J 15(3):553–555PubMedGoogle Scholar
  38. 38.
    Carta L et al (2009) p38 MAPK is an early determinant of promiscuous Smad2/3 signaling in the aortas of fibrillin-1 (Fbn1)-null mice. J Biol Chem 284(9):5630–5636PubMedGoogle Scholar
  39. 39.
    Yamashita M et al (2008) TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. Mol Cell 31(6):918–924PubMedCentralPubMedGoogle Scholar
  40. 40.
    Sorrentino A et al (2008) The type-I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat Cell Biol 10(10):1199–1207PubMedGoogle Scholar
  41. 41.
    Lee MK et al (2007) TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J 26(17):3957–3967PubMedGoogle Scholar
  42. 42.
    Wilkes MC et al (2005) Transforming growth factor-beta activation of phosphatidylinositol 3-kinase is independent of Smad2 and Smad3 and regulates fibroblast responses via p21-activated kinase-2. Cancer Res 65(22):10431–10440PubMedGoogle Scholar
  43. 43.
    Bertolino P et al (2005) Transforming growth factor-beta signal transduction in angiogenesis and vascular disorders. Chest 128(6 Suppl):585S–590SPubMedGoogle Scholar
  44. 44.
    Massague J (2000) How cells read TGF-beta signals. Nat Rev Mol Cell Biol 1(3):169–178PubMedGoogle Scholar
  45. 45.
    Ignotz RA, Massague J (1986) Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem 261(9):4337–4345PubMedGoogle Scholar
  46. 46.
    Yan C, Boyd DD (2007) Regulation of matrix metalloproteinase gene expression. J Cell Physiol 211(1):19–26PubMedGoogle Scholar
  47. 47.
    Kwak HJ et al (2006) Transforming growth factor-beta1 induces tissue inhibitor of metalloproteinase-1 expression via activation of extracellular signal-regulated kinase and Sp1 in human fibrosarcoma cells. Mol Cancer Res MCR 4(3):209–220Google Scholar
  48. 48.
    Kim ES, Kim MS, Moon A (2004) TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells. Int J Oncol 25(5):1375–1382PubMedGoogle Scholar
  49. 49.
    Laiho M, Saksela O, Keski-Oja J (1986) Transforming growth factor beta alters plasminogen activator activity in human skin fibroblasts. Exp Cell Res 164(2):399–407PubMedGoogle Scholar
  50. 50.
    Jones JA, Spinale FG, Ikonomidis JS (2009) Transforming growth factor-beta signaling in thoracic aortic aneurysm development: a paradox in pathogenesis. J Vasc Res 46(2):119–137PubMedCentralPubMedGoogle Scholar
  51. 51.
    Selvamurugan N et al (2004) Transforming growth factor-beta 1 regulation of collagenase-3 expression in osteoblastic cells by cross-talk between the Smad and MAPK signaling pathways and their components, Smad2 and Runx2. J Biol Chem 279(18):19327–19334PubMedGoogle Scholar
  52. 52.
    Pignolo RJ, Shore EM, Kaplan FS (2011) Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet J Rare Dis 6:80PubMedCentralPubMedGoogle Scholar
  53. 53.
    Werner S, Alzheimer C (2006) Roles of activin in tissue repair, fibrosis, and inflammatory disease. Cytokine Growth Factor Rev 17(3):157–171PubMedGoogle Scholar
  54. 54.
    Milewicz DM, Regalado E (1993) Thoracic aortic aneurysms and aortic dissections. In: Pagon RA (ed) Gene reviews. University of Washington, SeattleGoogle Scholar
  55. 55.
    Attias D et al (2009) Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders. Circulation 120(25):2541–2549PubMedGoogle Scholar
  56. 56.
    von Kodolitsch Y et al (2004) Chest radiography for the diagnosis of acute aortic syndrome. Am J Med 116(2):73–77Google Scholar
  57. 57.
    Bruno L et al (1984) Cardiac, skeletal, and ocular abnormalities in patients with Marfan’s syndrome and in their relatives. Comparison with the cardiac abnormalities in patients with kyphoscoliosis. Br Heart J 51(2):220–230PubMedCentralPubMedGoogle Scholar
  58. 58.
    Pannu H, Tran-Fadulu V, Milewicz DM (2005) Genetic basis of thoracic aortic aneurysms and aortic dissections. Am J Med Genet C Semin Med Genet 139C(1):10–16PubMedGoogle Scholar
  59. 59.
    Loeys BL et al (2006) Aneurysm syndromes caused by mutations in the TGF-beta receptor. New Engl J Med 355(8):788–798PubMedGoogle Scholar
  60. 60.
    Biddinger A et al (1997) Familial thoracic aortic dilatations and dissections: a case control study. J Vasc Surg 25(3):506–511PubMedGoogle Scholar
  61. 61.
    Hagan PG et al (2000) The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease. JAMA 283(7):897–903PubMedGoogle Scholar
  62. 62.
    Guo DC et al (2009) Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. Am J Hum Genet 84(5):617–627PubMedCentralPubMedGoogle Scholar
  63. 63.
    Milewicz DM et al (2010) De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction. Am J Med Genet A 152A(10):2437–2443PubMedCentralPubMedGoogle Scholar
  64. 64.
    Loscalzo ML et al (2007) Familial thoracic aortic dilation and bicommissural aortic valve: a prospective analysis of natural history and inheritance. Am J Med Genet A 143A(17):1960–1967PubMedGoogle Scholar
  65. 65.
    Zhu L et al (2006) Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet 38(3):343–349PubMedGoogle Scholar
  66. 66.
    Isselbacher EM (2005) Thoracic and abdominal aortic aneurysms. Circulation 111(6):816–828PubMedGoogle Scholar
  67. 67.
    Denton CP et al (2003) Fibroblast-specific expression of a kinase-deficient type-II transforming growth factor beta (TGFbeta) receptor leads to paradoxical activation of TGFbeta signaling pathways with fibrosis in transgenic mice. J Biol Chem 278(27):25109–25119PubMedGoogle Scholar
  68. 68.
    Wong SH et al (2000) Endoglin expression on human microvascular endothelial cells association with betaglycan and formation of higher order complexes with TGF-beta signalling receptors. Eur J Biochem/FEBS 267(17):5550–5560Google Scholar
  69. 69.
    Di Guglielmo GM et al (2003) Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Nat Cell Biol 5(5):410–421PubMedGoogle Scholar
  70. 70.
    Nakao A et al (1997) Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 389(6651):631–635PubMedGoogle Scholar
  71. 71.
    van de Laar IM et al (2011) Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet 43(2):121–126PubMedGoogle Scholar
  72. 72.
    Loeys B, De Paepe A (2008) New insights in the pathogenesis of aortic aneurysms. Verh K Acad Geneeskd Belg 70(2):69–84PubMedGoogle Scholar
  73. 73.
    Coucke PJ et al (2006) Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat Genet 38(4):452–457PubMedGoogle Scholar
  74. 74.
    Shprintzen RJ, Goldberg RB (1982) A recurrent pattern syndrome of craniosynostosis associated with arachnodactyly and abdominal hernias. J Craniofac Genet Dev Biol 2(1):65–74PubMedGoogle Scholar
  75. 75.
    Greally MT et al (1998) Shprintzen-Goldberg syndrome: a clinical analysis. Am J Med Genet 76(3):202–212PubMedGoogle Scholar
  76. 76.
    Akutsu K et al (2007) Phenotypic heterogeneity of Marfan-like connective tissue disorders associated with mutations in the transforming growth factor-beta receptor genes. Circ J 71(8):1305–1309PubMedGoogle Scholar
  77. 77.
    Greally MT (1993) Shprintzen-Goldberg syndrome. In: Pagon RA et al (eds) Gene reviews. University of Washington, SeattleGoogle Scholar
  78. 78.
    Robinson PN et al (2005) Shprintzen-Goldberg syndrome: fourteen new patients and a clinical analysis. Am J Med Genet A 135(3):251–262PubMedGoogle Scholar
  79. 79.
    Ades LC et al (1995) Distinct skeletal abnormalities in four girls with Shprintzen-Goldberg syndrome. Am J Med Genet 57(4):565–572PubMedGoogle Scholar
  80. 80.
    Ades LC et al (2006) FBN1, TGFBR1, and the Marfan-craniosynostosis/mental retardation disorders revisited. Am J Med Genet A 140(10):1047–1058PubMedGoogle Scholar
  81. 81.
    Ng CM (2004) TGF- -dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J Clin Invest 114(11):1586–1592PubMedCentralPubMedGoogle Scholar
  82. 82.
    Girdauskas E et al (2011) Transforming growth factor-beta receptor type-II mutation in a patient with bicuspid aortic valve disease and intraoperative aortic dissection. Ann Thorac Surg 91(5):e70–e71PubMedGoogle Scholar
  83. 83.
    Rendu H (1896) Epistaxis repetees chez un sujet porteur de petits angiomes cutanes et muquez. Gazette des Hopitaux Civils et Militaires (Paris) 135:1322Google Scholar
  84. 84.
    Osler W (1901) On a family form of recurring epistaxis, associated with multiple telangectases of the skin and mucous membranes. Bull Johns Hopkins Hosp 12:333Google Scholar
  85. 85.
    Weber F (1907) Multiple hereditary developmental angiomata (telangiectases) of the skin and mucous membranes associated with recurring hemorrhages. Lancet 2:160–162Google Scholar
  86. 86.
    Kjeldsen AD, Vase P, Green A (1999) Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients. J Intern Med 245(1):31–39PubMedGoogle Scholar
  87. 87.
    Bideau A et al (1989) Epidemiological investigation of Rendu-Osler disease in France: its geographical distribution and prevalence. Popul Engl Sel 44(1):3–22Google Scholar
  88. 88.
    Shovlin CL et al (2008) Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia. Thorax 63(3):259–266PubMedGoogle Scholar
  89. 89.
    Bourdeau A, Dumont DJ, Letarte M (1999) A murine model of hereditary hemorrhagic telangiectasia. J Clin Invest 104(10):1343–1351PubMedCentralPubMedGoogle Scholar
  90. 90.
    Wallace GM, Shovlin CL (2000) A hereditary haemorrhagic telangiectasia family with pulmonary involvement is unlinked to the known HHT genes, endoglin and ALK-1. Thorax 55(8):685–690PubMedGoogle Scholar
  91. 91.
    Cole SG et al (2005) A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5. J Med Genet 42(7):577–582PubMedGoogle Scholar
  92. 92.
    Plauchu H et al (1989) Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet 32(3):291–297PubMedGoogle Scholar
  93. 93.
    Pasculli G et al (2005) Capillaroscopy of the dorsal skin of the hands in hereditary hemorrhagic telangiectasia. QJM 98(10):757–763PubMedGoogle Scholar
  94. 94.
    Fulbright RK et al (1998) MR of hereditary hemorrhagic telangiectasia: prevalence and spectrum of cerebrovascular malformations. AJNR Am J Neuroradiol 19(3):477–484PubMedGoogle Scholar
  95. 95.
    Cottin V et al (2004) Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia. Am J Respir Crit Care Med 169(9):994–1000PubMedGoogle Scholar
  96. 96.
    Piantanida M et al (1996) Hereditary haemorrhagic telangiectasia with extensive liver involvement is not caused by either HHT1 or HHT2. J Med Genet 33(6):441–443PubMedGoogle Scholar
  97. 97.
    Govani FS, Shovlin CL (2009) Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur J Hum Genet 17(7):860–871PubMedGoogle Scholar
  98. 98.
    Shovlin CL et al (2007) Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): association with venous thromboembolism. Thromb Haemost 98(5):1031–1039PubMedGoogle Scholar
  99. 99.
    Cirulli A et al (2006) 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 12(10):1209–1215PubMedGoogle Scholar
  100. 100.
    Shovlin CL et al (2000) Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 91(1):66–67PubMedGoogle Scholar
  101. 101.
    Faughnan ME et al (2011) International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet 48(2):73–87PubMedGoogle Scholar
  102. 102.
    McAllister KA et al (1994) Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 8(4):345–351PubMedGoogle Scholar
  103. 103.
    Berg JN et al (1997) The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet 61(1):60–67PubMedCentralPubMedGoogle Scholar
  104. 104.
    Johnson DW et al (1996) Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 13(2):189–195PubMedGoogle Scholar
  105. 105.
    Andrabi S et al (2011) SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction. Am J Med Genet A 155A(5):1165–1169PubMedGoogle Scholar
  106. 106.
    Letarte M et al (2005) Reduced endothelial secretion and plasma levels of transforming growth factor-beta1 in patients with hereditary hemorrhagic telangiectasia type 1. Cardiovasc Res 68(1):155–164PubMedGoogle Scholar
  107. 107.
    Roman BL et al (2002) Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels. Development 129(12):3009–3019PubMedGoogle Scholar
  108. 108.
    Oh SP et al (2000) Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A 97(6):2626–2631PubMedCentralPubMedGoogle Scholar
  109. 109.
    Seki T, Yun J, Oh SP (2003) Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling. Circ Res 93(7):682–689PubMedGoogle Scholar
  110. 110.
    Stefansson S et al (2001) Inhibition of angiogenesis in vivo by plasminogen activator inhibitor-1. J Biol Chem 276(11):8135–8141PubMedGoogle Scholar
  111. 111.
    Fernandez LA et al (2005) Blood outgrowth endothelial cells from Hereditary Haemorrhagic Telangiectasia patients reveal abnormalities compatible with vascular lesions. Cardiovasc Res 68(2):235–248Google Scholar
  112. 112.
    Goumans MJ et al (2003) Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK-5 signaling. Mol Cell 12(4):817–828PubMedGoogle Scholar
  113. 113.
    Davies RJ et al (2012) BMP type-II receptor deficiency confers resistance to growth inhibition by TGF-beta in pulmonary artery smooth muscle cells: role of proinflammatory cytokines. Am J Physiol Lung Cell Mol Physiol 302(6):L604–L615PubMedGoogle Scholar
  114. 114.
    West J et al (2004) Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle. Circ Res 94(8):1109–1114PubMedGoogle Scholar
  115. 115.
    Kimura N et al (2000) BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. J Biol Chem 275(23):17647–17652PubMedGoogle Scholar
  116. 116.
    Trembath RC et al (2001) Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. New Engl J Med 345(5):325–334PubMedGoogle Scholar
  117. 117.
    You HJ et al (2007) The type-III TGF-beta receptor signals through both Smad3 and the p38 MAP kinase pathways to contribute to inhibition of cell proliferation. Carcinogenesis 28(12):2491–2500PubMedGoogle Scholar
  118. 118.
    Hawinkels LJ, Ten Dijke P (2011) Exploring anti-TGF-beta therapies in cancer and fibrosis. Growth Factors 29(4):140–152PubMedGoogle Scholar
  119. 119.
    Rico MC et al (2008) Thrombospondin-1 and transforming growth factor beta are pro-inflammatory molecules in rheumatoid arthritis. Transl Res 152(2):95–98PubMedCentralPubMedGoogle Scholar
  120. 120.
    Rico MC et al (2010) The axis of thrombospondin-1, transforming growth factor beta and connective tissue growth factor: an emerging therapeutic target in rheumatoid arthritis. Curr Vasc Pharmacol 8(3):338–343PubMedGoogle Scholar
  121. 121.
    Wahl SM, Chen W (2005) Transforming growth factor-beta-induced regulatory T cells referee inflammatory and autoimmune diseases. Arthritis Res Ther 7(2):62–68PubMedCentralPubMedGoogle Scholar
  122. 122.
    Ohtsuka K et al (1998) Decreased production of TGF-beta by lymphocytes from patients with systemic lupus erythematosus. J Immunol 160(5):2539–2545PubMedGoogle Scholar
  123. 123.
    Mageed RA, Prud’homme GJ (2003) Immunopathology and the gene therapy of lupus. Gene Ther 10(10):861–874PubMedGoogle Scholar
  124. 124.
    Hiratzka LF et al (2010) ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation 121(13):e266–e369PubMedGoogle Scholar
  125. 125.
    Coady MA, Rizzo JA, Elefteriades JA (1999) Developing surgical intervention criteria for thoracic aortic aneurysms. Cardiol Clin 17(4):827–839PubMedGoogle Scholar
  126. 126.
    Coady MA et al (1999) Surgical intervention criteria for thoracic aortic aneurysms: a study of growth rates and complications. Ann Thorac Surg 67(6):1922–1926, discussion 1953–1958PubMedGoogle Scholar
  127. 127.
    Elefteriades JA (2002) Natural history of thoracic aortic aneurysms: indications for surgery, and surgical versus nonsurgical risks. Ann Thorac Surg 74(5):S1877–S1880, discussion S1892–S1898PubMedGoogle Scholar
  128. 128.
    Lobato AC, Puech-Leao P (1998) Predictive factors for rupture of thoracoabdominal aortic aneurysm. J Vasc Surg 27(3):446–453PubMedGoogle Scholar
  129. 129.
    Svensson LG et al (1989) Appraisal of adjuncts to prevent acute renal failure after surgery on the thoracic or thoracoabdominal aorta. J Vasc Surg 10(3):230–239PubMedGoogle Scholar
  130. 130.
    Svensson LG et al (1993) Experience with 1509 patients undergoing thoracoabdominal aortic operations. J Vasc Surg 17(2):357–368, discussion 368–370PubMedGoogle Scholar
  131. 131.
    Bobik A (2006) Transforming growth factor-betas and vascular disorders. Arterioscler Thromb Vasc Biol 26(8):1712–1720PubMedGoogle Scholar
  132. 132.
    Ikonomidis JS et al (2006) Expression of matrix metalloproteinases and endogenous inhibitors within ascending aortic aneurysms of patients with Marfan syndrome. Circulation 114(1 Suppl):I365–I370PubMedGoogle Scholar
  133. 133.
    Kapoun AM et al (2006) Transforming growth factor-beta receptor type 1 (TGFbetaRI) kinase activity but not p38 activation is required for TGFbetaRI-induced myofibroblast differentiation and profibrotic gene expression. Mol Pharmacol 70(2):518–531PubMedGoogle Scholar
  134. 134.
    Hu Y et al (2006) Role of extracellular signal-regulated kinase, p38 kinase, and activator protein-1 in transforming growth factor-beta1-induced alpha smooth muscle actin expression in human fetal lung fibroblasts in vitro. Lung 184(1):33–42PubMedGoogle Scholar
  135. 135.
    Greenberg RK et al (2008) Contemporary analysis of descending thoracic and thoracoabdominal aneurysm repair: a comparison of endovascular and open techniques. Circulation 118(8):808–817PubMedGoogle Scholar
  136. 136.
    Makaroun MS et al (2008) Five-year results of endovascular treatment with the Gore TAG device compared with open repair of thoracic aortic aneurysms. J Vasc Surg 47(5):912–918PubMedGoogle Scholar
  137. 137.
    Yetman AT, Bornemeier RA, McCrindle BW (2005) Usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. Am J Cardiol 95(9):1125–1127PubMedGoogle Scholar
  138. 138.
    Kubo A et al (2000) Angiotensin II regulates the cell cycle of vascular smooth muscle cells from SHR. Am J Hypertens 13(10):1117–1124PubMedGoogle Scholar
  139. 139.
    Habashi JP et al (2006) Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312(5770):117–121PubMedCentralPubMedGoogle Scholar
  140. 140.
    Habashi JP et al (2011) Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science 332(6027):361–365PubMedCentralPubMedGoogle Scholar
  141. 141.
    Judge DP et al (2011) Mitral valve disease in Marfan syndrome and related disorders. J Cardiovasc Transl Res 4(6):741–747PubMedGoogle Scholar
  142. 142.
    Holm TM et al (2011) Noncanonical TGFbeta signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science 332(6027):358–361PubMedCentralPubMedGoogle Scholar
  143. 143.
    Milewicz DM, Carlson AA, Regalado ES (2010) Genetic testing in aortic aneurysm disease: PRO. Cardiol Clin 28(2):191–197PubMedCentralPubMedGoogle Scholar
  144. 144.
    Sood S et al (1996) Mutation in fibrillin-1 and the Marfanoid-craniosynostosis (Shprintzen-Goldberg) syndrome. Nat Genet 12(2):209–211PubMedGoogle Scholar
  145. 145.
    Kosaki K et al (2006) Molecular pathology of Shprintzen-Goldberg syndrome. Am J Med Genet A 140(1):104–108, author reply 109–110PubMedGoogle Scholar
  146. 146.
    van Steensel MA et al (2008) Shprintzen-Goldberg syndrome associated with a novel missense mutation in TGFBR2. Exp Dermatol 17(4):362–365PubMedGoogle Scholar
  147. 147.
    Stheneur C et al (2008) Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype-Investigations in 457 patients with Marfan syndrome type-I and II, Loeys-Dietz syndrome and related disorders. Hum Mutat 29(11):E284–E295PubMedGoogle Scholar
  148. 148.
    Kuhnel TS et al (2005) Clinical strategy in hereditary hemorrhagic telangiectasia. Am J Rhinol 19(5):508–513PubMedGoogle Scholar
  149. 149.
    Buscarini E et al (2006) Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations. Liver Int 26(9):1040–1046PubMedGoogle Scholar
  150. 150.
    Cohen JH et al (2005) Cost comparison of genetic and clinical screening in families with hereditary hemorrhagic telangiectasia. Am J Med Genet A 137(2):153–160PubMedGoogle Scholar
  151. 151.
    Abdalla SA, Letarte M (2006) Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet 43(2):97–110PubMedGoogle Scholar
  152. 152.
    Rifkin DB, Todorovic V (2010) Bone matrix to growth factors: location, location, location. J Cell Biol 190(6):949–951PubMedGoogle Scholar
  153. 153.
    Atsawasuwan P et al (2008) Lysyl oxidase binds transforming growth factor-beta and regulates its signaling via amine oxidase activity. J Biol Chem 283(49):34229–34240PubMedGoogle Scholar
  154. 154.
    Fernandez LA et al (2006) Hereditary hemorrhagic telangiectasia, a vascular dysplasia affecting the TGF-beta signaling pathway. Clin Med Res 4(1):66–78Google Scholar
  155. 155.
    Gleason TG (2005) Heritable disorders predisposing to aortic dissection. Semin Thorac Cardiovasc Surg 17(3):274–281PubMedGoogle Scholar
  156. 156.
    Pannu H et al (2005) Mutations in transforming growth factor-beta receptor type-II cause familial thoracic aortic aneurysms and dissections. Circulation 112(4):513–520PubMedGoogle Scholar
  157. 157.
    Callewaert BL et al (2008) Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. Hum Mutat 29(1):150–158PubMedGoogle Scholar
  158. 158.
    van de Laar IM et al (2012) Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J Med Genet 49(1):47–57PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Jason B. Wheeler
    • 1
  • John S. Ikonomidis
    • 1
  • Jeffrey A. Jones
    • 1
    • 2
    Email author
  1. 1.Division of Cardiothoracic SurgeryMedical University of South CarolinaCharlestonUSA
  2. 2.Ralph H. Johnson Veterans Affairs Medical CenterCharlestonUSA

Personalised recommendations