, Volume 11, Issue 1, pp 79–89 | Cite as

Endoglin in angiogenesis and vascular diseases

  • Peter ten Dijke
  • Marie-José Goumans
  • Evangelia Pardali
Original paper


Endoglin is a transmembrane auxillary receptor for transforming growth factor-β (TGF-β) that is predominantly expressed on proliferating endothelial cells. Endoglin deficient mice die during midgestation due to cardiovascular defects. Mutations in endoglin and activin receptor-like kinase 1 (ALK1), an endothelial specific TGF-β type I receptor, have been linked to hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vascular dysplasia characterized by telangiectases and arteriovenous malformations. Endoglin heterozygote mice develop HHT-like vascular abnormalities, have impaired tumor and post-ischemic angiogenesis and demonstrate an endothelial nitric oxide synthase-dependent deterioration in the regulation of vascular tone. In pre-eclampsia, placenta-derived endoglin has been shown to be strongly upregulated and high levels of soluble endoglin are released into the circulation. Soluble endoglin was found to cooperate with a soluble form of vascular endothelial growth factor receptor 1 in the pathogenesis of pre-eclampsia by inducing endothelial cell dysfunction. Endoglin is highly expressed in tumor-associated endothelium, and endoglin antibodies have been successfully used to target activated endothelial cells and elicit anti-angiogenic effects in tumor mouse models. These exciting advances provide opportunities for the development of new therapies for diseases with vascular abnormalities.


Angiogenesis BMP Endothelial cells Hereditary hemorrhagic telangiectasia Signal transduction Smad TGF-β 


  1. 1.
    Quackenbush EJ, Gougos A, Baumal R, Letarte M (2006) Differential localization within human kidney of five membrane proteins expressed on acute lymphoblastic leukemia cells. J Immunol 136:118–124Google Scholar
  2. 2.
    Gougos A, Letarte M (1990) Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J Biol Chem 265:8361–8364PubMedGoogle Scholar
  3. 3.
    Burrows FJ, Derbyshire EJ, Tazzari PL, Amlot P, Gazdar AF, King SW, Letarte M, Vitetta ES, Thorpe PE (1995) Up-regulation of endoglin on vascular endothelial cells in human solid tumors: implications for diagnosis and therapy. Clin Cancer Res 1:1623–1634PubMedGoogle Scholar
  4. 4.
    Miller DW, Graulich W, Karges B, Stahl S, Ernst M, Ramaswamy A, Sedlacek HH, Müller R, Adamkiewicz J (1999) Elevated expression of endoglin, a component of the TGF-β-receptor complex, correlates with proliferation of tumor endothelial cells. Int J Cancer 81:568–572PubMedGoogle Scholar
  5. 5.
    Fonsatti E, Jekunen AP, Kairemo KJ, Coral S, Snellman M, Nicotra MR, Natali PG, Altomonte M, Maio M (2000) Endoglin is a suitable target for efficient imaging of solid tumors: in vivo evidence in a canine mammary carcinoma model. Clin Cancer Res 6:2037–2043PubMedGoogle Scholar
  6. 6.
    Cheifetz S, Bellón T, Calés C, Vera S, Bernabeu C, Massagué J, Letarte M (1992) Endoglin is a component of the transforming growth factor-β receptor system in human endothelial cells. J Biol Chem 267:19027–19030PubMedGoogle Scholar
  7. 7.
    McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J et al (1994) Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 8:345–351PubMedGoogle Scholar
  8. 8.
    Li DY, Sorensen LK, Brooke BS, Urness LD, Davis EC, Taylor DG, Boak BB, Wendel DP (1999) Defective angiogenesis in mice lacking endoglin. Science 284:1534–1537PubMedGoogle Scholar
  9. 9.
    Bourdeau A, Dumont DJ, Letarte M (1999) A murine model of hereditary hemorrhagic telangiectasia. J Clin Invest 104:1343–1351PubMedCrossRefGoogle Scholar
  10. 10.
    Arthur HM, Ure J, Smith AJ, Renforth G, Wilson DI, Torsney E, Charlton R, Parums DV, Jowett T, Marchuk DA, Burn J, Diamond AG (2000) Endoglin, an ancillary TGFβ receptor, is required for extraembryonic angiogenesis and plays a key role in heart development. Dev Biol 217:42–53PubMedGoogle Scholar
  11. 11.
    Jerkic M, Rodríguez-Barbero A, Prieto M, Toporsian M, Pericacho M, Rivas-Elena JV, Obreo J, Wang A, Pérez-Barriocanal F, Arévalo M, Bernabéu C, Letarte M, López-Novoa JM (2006) Reduced angiogenic responses in adult Endoglin heterozygous mice. Cardiovasc Res 69:845–854PubMedGoogle Scholar
  12. 12.
    Düwel A, Eleno N, Jerkic M, Arevalo M, Bolaños JP, Bernabeu C, López-Novoa JM (2007) Reduced tumor growth and angiogenesis in endoglin-haploinsufficient mice. Tumour Biol 28:1–8PubMedGoogle Scholar
  13. 13.
    Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D’Amore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP, Letarte M, Karumanchi SA (2006) Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2:642–649Google Scholar
  14. 14.
    ten Dijke P, Arthur HM (2007) Extracellular control of TGFβ signalling in vascular development and disease. Nat Rev Mol Cell Biol 8:857–869PubMedGoogle Scholar
  15. 15.
    Blobe GC, Schiemann WP, Lodish HF (2000) Role of transforming growth factor β in human disease. N Engl J Med 342:1350–1358PubMedGoogle Scholar
  16. 16.
    Heldin CH, Miyazono K, ten Dijke P (1997) TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature 390:465–471PubMedGoogle Scholar
  17. 17.
    Schmierer B, Hill CS (2007) TGFβ-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 8:970–982PubMedGoogle Scholar
  18. 18.
    Franzén P, ten Dijke P, Ichijo H, Yamashita H, Schulz P, Heldin CH, Miyazono K (1993) Cloning of a TGFβ type I receptor that forms a heteromeric complex with the TGFβ type II receptor. Cell 75:681–692PubMedGoogle Scholar
  19. 19.
    Goumans MJ, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, ten Dijke P (2002) Balancing the activation state of the endothelium via two distinct TGF-β type I receptors. EMBO J 21:1743–1753PubMedGoogle Scholar
  20. 20.
    Mathews LS, Vale WW (1991) Expression cloning of an activin receptor, a predicted transmembrane serine kinase. Cell 65:973–982PubMedGoogle Scholar
  21. 21.
    Attisano L, Wrana JL, Montalvo E, Massagué J (1996) Activation of signalling by the activin receptor complex. Mol Cell Biol 16:1066–1073PubMedGoogle Scholar
  22. 22.
    ten Dijke P, Yamashita H, Sampath TK, Reddi AH, Estevez M, Riddle DL, Ichijo H, Heldin C-H, Miyazono K (1994) Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J Biol Chem 269:16985–16988PubMedGoogle Scholar
  23. 23.
    Liu F, Ventura F, Doody J, Massagué J (1995) Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Mol Cell Biol 15:3479–3486PubMedGoogle Scholar
  24. 24.
    Rosenzweig BL, Imamura T, Okadome T, Cox GN, Yamashita H, ten Dijke P, Heldin CH, Miyazono K (1995) Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc Natl Acad Sci USA 92:7632–7636PubMedGoogle Scholar
  25. 25.
    Yamashita H, ten Dijke P, Huylebroeck D, Sampath TK, Andries M, Smith JC, Heldin C-H, Miyazono K (1995) Osteogenic protein-1 binds to activin type II receptors and induces certain activin-like effects. J Cell Biol 130:217–226PubMedGoogle Scholar
  26. 26.
    Wrana JL, Attisano L, Wieser R, Ventura F, Massagué J (1994) Mechanism of activation of the TGF-β receptor. Nature 370:341–347PubMedGoogle Scholar
  27. 27.
    Abdollah S, Macías-Silva M, Tsukazaki T, Hayashi H, Attisano L, Wrana JL (1997) TβRI phosphorylation of Smad2 on Ser465 and Ser467 is required for Smad2-Smad4 complex formation and signaling. J Biol Chem 272:27678–27685PubMedGoogle Scholar
  28. 28.
    Souchelnytskyi S, Tamaki K, Engström U, Wernstedt C, ten Dijke P, Heldin C-H (1997) Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-β signaling. J Biol Chem 272:28107–28115PubMedGoogle Scholar
  29. 29.
    Hoodless PA, Haerry T, Abdollah S, Stapleton M, O’Connor MB, Attisano L, Wrana JL (1986) MADR1, a MAD-related protein that functions in BMP2 signaling pathways. Cell 85:489–500Google Scholar
  30. 30.
    Eppert K, Scherer SW, Ozcelik H, Pirone R, Hoodless P, Kim H, Tsui LC, Bapat B, Gallinger S, Andrulis IL, Thomsen GH, Wrana JL, Attisano L (1996) MADR2 maps to 18q21 and encodes a TGFβ-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell 86:543–552PubMedGoogle Scholar
  31. 31.
    Zhang Y, Feng X, We R, Derynck R (1996) Receptor-associated Mad homologues synergize as effectors of the TGF-β response. Nature 383:168–172PubMedGoogle Scholar
  32. 32.
    Lagna G, Hata A, Hemmati-Brivanlou A, Massagué J (1996) Partnership between DPC4 and SMAD proteins in TGF-β signalling pathways. Nature 383:832–836PubMedGoogle Scholar
  33. 33.
    Liu F, Pouponnot C, Massagué J (1997) Dual role of the Smad4/DPC4 tumor suppressor in TGFβ-inducible transcriptional complexes. Genes Dev 11:3157–3167PubMedGoogle Scholar
  34. 34.
    Feng XH, Zhang Y, Wu RY, Derynck R (1998) The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-β-induced transcriptional activation. Genes Dev 12:2153–2163PubMedGoogle Scholar
  35. 35.
    Lastres P, Letamendía A, Zhang H, Rius C, Almendro N, Raab U, López LA, Langa C, Fabra A, Letarte M, Bernabéu C (1996) Endoglin modulates cellular responses to TGF-β1. J Cell Biol 133:1109–1121PubMedGoogle Scholar
  36. 36.
    Lebrin F, Deckers M, Bertolino P, tn Dijke P (2005) TGF-β receptor function in the endothelium. Cardiovasc Res 65:599–608PubMedGoogle Scholar
  37. 37.
    Pérez-Gómez E, Eleno N, López-Novoa JM, Ramirez JR, Velasco B, Letarte M, Bernabéu C, Quintanilla M (2005) Characterization of murine S-endoglin isoform and its effects on tumor development. Oncogene 24:4450–4461PubMedGoogle Scholar
  38. 38.
    Velasco S, Alvarez-Muñoz P, Pericacho M, ten Dijke P, Bernabeu C, Lopez-Novoa JM, Rodriguez-Barbero A (2008) L- and S-endoglin differentially modulate transforming growth factor β1 signaling mediated by ALK1 and ALK5 in L6E9 myoblasts. J Cell Sci (in press)Google Scholar
  39. 39.
    Wang XF, Lin HY, Ng-Eaton E, Downward J, Lodish HF, Weinberg RA (1991) Expression cloning and characterization of the TGF-β type III receptor. Cell 67:797–805PubMedGoogle Scholar
  40. 40.
    López-Casillas F, Cheifetz S, Doody J, Andres JL, Lane WS, Massagué J (1991) Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-β receptor system. Cell 67:785–795PubMedGoogle Scholar
  41. 41.
    López-Casillas F, Wrana JL, Massagué J (1993) Betaglycan presents ligand to the TGFβ signaling receptor. Cell 73:1435–1444PubMedGoogle Scholar
  42. 42.
    Letamendía A, Lastres P, Botella LM, Raab U, Langa C, Velasco B, Attisano L, Bernabeu C (1998) Role of endoglin in cellular responses to transforming growth factor-β. A comparative study with betaglycan. J Biol Chem 273:33011–33019PubMedGoogle Scholar
  43. 43.
    Wong SH, Hamel L, Chevalier S, Philip A (2000) Endoglin expression on human microvascular endothelial cells association with betaglycan and formation of higher order complexes with TGF-β signalling receptors. Eur J Biochem 267:5550–5560PubMedGoogle Scholar
  44. 44.
    Calabrò L, Fonsatti E, Bellomo G, Alonci A, Colizzi F, Sigalotti L, Altomonte M, Musolino C, Maio M (2003) Differential levels of soluble endoglin (CD105) in myeloid malignancies. J Cell Physiol 194:171–175PubMedGoogle Scholar
  45. 45.
    Li C, Guo B, Wilson PB, Stewart A, Byrne G, Bundred N, Kumar S (2000) Plasma levels of soluble CD105 correlate with metastasis in patients with breast cancer. Int J Cancer 89:122–126PubMedGoogle Scholar
  46. 46.
    Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai BM, Epstein FH, Romero R, Thadhani R, Karumanchi SA; CPEP Study Group (2006) Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 355:992–1005PubMedGoogle Scholar
  47. 47.
    Velasco-Loyden G, Arribas J, López-Casillas F (2004) The shedding of betaglycan is regulated by pervanadate and mediated by membrane type matrix metalloprotease-1. J Biol Chem 279:7721–7733PubMedGoogle Scholar
  48. 48.
    Yamashita H, Ichijo H, Grimsby S, Morén A, ten Dijke P, Miyazono K (1994) Endoglin forms a heteromeric complex with the signaling receptors for transforming growth factor-β. J Biol Chem 269:1995–2001PubMedGoogle Scholar
  49. 49.
    Bork P, Sander C (1992) A large domain common to sperm receptors (Zp2 and Zp3) and TGF-β type III receptor. FEBS Lett 300:237–240PubMedGoogle Scholar
  50. 50.
    Guerrero-Esteo M, Sanchez-Elsner T, Letamendia A, Bernabeu C (2002) Extracellular and cytoplasmic domains of endoglin interact with the transforming growth factor-β receptors I and II. J Biol Chem 277:29197–29209PubMedGoogle Scholar
  51. 51.
    Llorca O, Trujillo A, Blanco FJ, Bernabeu C (2007) Structural model of human endoglin, a transmembrane receptor responsible for hereditary hemorrhagic telangiectasia. J Mol Biol 365:694–705PubMedGoogle Scholar
  52. 52.
    Koleva RI, Conley BA, Romero D, Riley KS, Marto JA, Lux A, Vary CP (2006) Endoglin structure and function: Determinants of endoglin phosphorylation by transforming growth factor-β receptors. J Biol Chem 281:25110–25123PubMedGoogle Scholar
  53. 53.
    Bellón T, Corbí A, Lastres P, Calés C, Cebrián M, Vera S, Cheifetz S, Massague J, Letarte M, Bernabéu C (1993) Identification and expression of two forms of the human transforming growth factor-β-binding protein endoglin with distinct cytoplasmic regions. Eur J Immunol 23:2340–2345PubMedGoogle Scholar
  54. 54.
    van Laake LW, van den Driesche S, Post S, Feijen A, Jansen MA, Driessens MH, Mager JJ, Snijder RJ, Westermann CJ, Doevendans PA, van Echteld CJ, ten Dijke P, Arthur HM, Goumans MJ, Lebrin F, Mummery CL (2006) Endoglin has a crucial role in blood cell-mediated vascular repair. Circulation 114:2288–2297PubMedGoogle Scholar
  55. 55.
    Li C, Issa R, Kumar P, Hampson IN, Lopez-Novoa JM, Bernabeu C, Kumar S (2003) CD105 prevents apoptosis in hypoxic endothelial cells. J Cell Sci 116:2677–2685PubMedGoogle Scholar
  56. 56.
    Scharpfenecker M, van Dinther M, Liu Z, van Bezooijen RL, Zhao Q, Pukac L, Löwik CW, ten Dijke P (2007) BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. J Cell Sci 120:964–972PubMedGoogle Scholar
  57. 57.
    Ota T, Fujii M, Sugizaki T, Ishii M, Miyazawa K, Aburatani H, Miyazono K (2002) Targets of transcriptional regulation by two distinct type I receptors for transforming growth factor-β in human umbilical vein endothelial cells. J Cell Physiol 193:299–318PubMedGoogle Scholar
  58. 58.
    Li C, Guo B, Ding S, Rius C, Langa C, Kumar P, Bernabeu C, Kumar S (2003) TNFα down-regulates CD105 expression in vascular endothelial cells: a comparative study with TGFβ1. Anticancer Res 23:1189–1196PubMedGoogle Scholar
  59. 59.
    Botella LM, Sánchez-Elsner T, Rius C, Corbí A, Bernabéu C (2001) Identification of a critical Sp1 site within the endoglin promoter and its involvement in the transforming growth factor-β stimulation. J Biol Chem 276:34486–34494PubMedGoogle Scholar
  60. 60.
    Sánchez-Elsner T, Botella LM, Velasco B, Langa C, Bernabéu C (2002) Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-β pathways. J Biol Chem 277:43799–43808PubMedGoogle Scholar
  61. 61.
    Lastres P, Bellon T, Cabañas C, Sanchez-Madrid F, Acevedo A, Gougos A, Letarte M, Bernabeu C (1992) Regulated expression on human macrophages of endoglin, an Arg-Gly-Asp-containing surface antigen. Eur J Immunol 22:393–397PubMedGoogle Scholar
  62. 62.
    St-Jacques S, Forte M, Lye SJ, Letarte M (1994) Localization of endoglin, a transforming growth factor-β binding protein, and of CD44 and integrins in placenta during the first trimester of pregnancy. Biol Reprod 51:405–413PubMedGoogle Scholar
  63. 63.
    Conley BA, Smith JD, Guerrero-Esteo M, Bernabeu C, Vary CP (2000) Endoglin, a TGF-β receptor-associated protein, is expressed by smooth muscle cells in human atherosclerotic plaques. Atherosclerosis 153:323–335PubMedGoogle Scholar
  64. 64.
    Mancini ML, Verdi JM, Conley BA, Nicola T, Spicer DB, Oxburgh LH, Vary CP (2007) Endoglin is required for myogenic differentiation potential of neural crest stem cells. Dev Biol 308:520–533PubMedGoogle Scholar
  65. 65.
    Chen CZ, Li M, de Graaf D, Monti S, Göttgens B, Sanchez MJ, Lander ES, Golub TR, Green AR, Lodish HF (2002) Identification of endoglin as a functional marker that defines long-term repopulating hematopoietic stem cells. Proc Natl Acad Sci USA 99:15468–15473PubMedGoogle Scholar
  66. 66.
    Chen CZ, Li L, Li M, Lodish HF (2003) The endoglin(positive) sca-1(positive) rhodamine(low) phenotype defines a near-homogeneous population of long-term repopulating hematopoietic stem cells. Immunity 19:525–533PubMedGoogle Scholar
  67. 67.
    Perlingeiro RC (2007) Endoglin is required for hemangioblast and early hematopoietic development. Development 34:3041–3048Google Scholar
  68. 68.
    Moody JL, Singbrant S, Karlsson G, Blank U, Aspling M, Flygare J, Bryder D, Karlsson S (2007) Endoglin is not critical for hematopoietic stem cell engraftment and reconstitution but regulates adult erythroid development. Stem Cells 25:2809–2819PubMedGoogle Scholar
  69. 69.
    Altomonte M, Montagner R, Fonsatti E, Colizzi F, Cattarossi I, Brasoveanu LI, Nicotra MR, Cattelan A, Natali PG, Maio M (1996) Expression and structural features of endoglin (CD105), a transforming growth factor β1 and β3 binding protein, in human melanoma. Br J Cancer 74:1586–1591PubMedGoogle Scholar
  70. 70.
    Henriksen R, Gobl A, Wilander E, Oberg K, Miyazono K, Funa K (1995) Expression and prognostic significance of TGF-β isotypes, latent TGF-β1 binding protein, TGF-β type I and type II receptors, and endoglin in normal ovary and ovarian neoplasms. Lab Invest 73:213–220PubMedGoogle Scholar
  71. 71.
    Jovanovic B, Huang S, Liu YQ, Naguib KN, Bergan RC (2001) Am J PharmacoGenomics 1:145–152PubMedGoogle Scholar
  72. 72.
    Liu Y, Jovanovic B, Pins M, Lee C, Bergan RC (2002) Over expression of endoglin in human prostate cancer suppresses cell detachment, migration and invasion. Oncogene 21:8272–8281PubMedGoogle Scholar
  73. 73.
    Craft CS, Romero D, Vary CP, Bergan RC (2007) Endoglin inhibits prostate cancer motility via activation of the ALK2-Smad1 pathway. Oncogene 26:7240–7250PubMedGoogle Scholar
  74. 74.
    Quintanilla M, Ramirez JR, Pérez-Gómez E, Romero D, Velasco B, Letarte M, López-Novoa JM, Bernabéu C (2003) Expression of the TGF-β coreceptor endoglin in epidermal keratinocytes and its dual role in multistage mouse skin carcinogenesis. Oncogene 22:5976–5985PubMedGoogle Scholar
  75. 75.
    Lux A, Attisano L, Marchuk DA (1999) Assignment of transforming growth factor β1 and β3 and a third new ligand to the type I receptor ALK-1. J Biol Chem 274:9984–9992PubMedGoogle Scholar
  76. 76.
    Barbara NP, Wrana JL, Letarte M (1999) 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 274:584–594PubMedGoogle Scholar
  77. 77.
    Goumans MJ, Valdimarsdottir G, Itoh S, Lebrin F, Larsson J, Mummery C, Karlsson S, ten Dijke P (2003) Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFβ/ALK5 signaling. Mol Cell 12:817–828PubMedGoogle Scholar
  78. 78.
    Guo B, Slevin M, Li C, Parameshwar S, Liu D, Kumar P, Bernabeu C, Kumar S (2004) CD105 inhibits transforming growth factor-β-Smad3 signalling. Anticancer Res 24:1337–1345PubMedGoogle Scholar
  79. 79.
    Scherner O, Meurer SK, Tihaa L, Gressner AM, Weiskirchen R (2007) Endoglin differentially modulates antagonistic transforming growth factor-β1 and BMP-7 signaling. J Biol Chem 282:13934–13943PubMedGoogle Scholar
  80. 80.
    Lebrin F, Goumans MJ, Jonker L, Carvalho RL, Valdimarsdottir G, Thorikay M, Mummery C, Arthur HM, ten Dijke P (2004) Endoglin promotes endothelial cell proliferation and TGF-β/ALK1 signal transduction. EMBO J 23:4018–4028PubMedGoogle Scholar
  81. 81.
    Li C, Hampson IN, Hampson L, Kumar P, Bernabeu C, Kumar S (2000) CD105 antagonizes the inhibitory signaling of transforming growth factor β1 on human vascular endothelial cells. FASEB J 14:55–64PubMedGoogle Scholar
  82. 82.
    Blanco FJ, Santibanez JF, Guerrero-Esteo M, Langa C, Vary CP, Bernabeu C (2005) Interaction and functional interplay between endoglin and ALK-1, two components of the endothelial transforming growth factor-β receptor complex. J Cell Physiol 204:574–584PubMedGoogle Scholar
  83. 83.
    She X, Matsuno F, Harada N, Tsai H, Seon BK (2004) Synergy between anti-endoglin (CD105) monoclonal antibodies and TGF-β in suppression of growth of human endothelial cells. Int J Cancer 108:251–257PubMedGoogle Scholar
  84. 84.
    Fernandez-L A, Sanz-Rodriguez F, Zarrabeitia R, Pérez-Molino A, Hebbel RP, Nguyen J, Bernabéu C, Botella LM (2005) Blood outgrowth endothelial cells from Hereditary Haemorrhagic Telangiectasia patients reveal abnormalities compatible with vascular lesions. Cardiovasc Res 68:235–248PubMedGoogle Scholar
  85. 85.
    Pece-Barbara N, Vera S, Kathirkamathamby K, Liebner S, Di Guglielmo GM, Dejana E, Wrana JL, Letarte M (2005) Endoglin null endothelial cells proliferate faster and are more responsive to transforming growth factor β1 with higher affinity receptors and an activated ALK1 pathway. J Biol Chem 280:27800–27808PubMedGoogle Scholar
  86. 86.
    Toporsian M, Gros R, Kabir MG, Vera S, Govindaraju K, Eidelman DH, Husain M, Letarte M (2005) A role for endoglin in coupling eNOS activity and regulating vascular tone revealed in hereditary hemorrhagic telangiectasia. Circ Res 96:684–692PubMedGoogle Scholar
  87. 87.
    Santibanez JF, Blanco FJ, Garrido-Martin EM, Sanz-Rodriguez F, Del Pozo MA, Bernabeu C (2008) Caveolin-1 interacts and cooperates with the transforming growth factor-β type I receptor ALK1 in endothelial caveolae. Cardiovasc Res (in press)Google Scholar
  88. 88.
    Razani B, Zhang XL, Bitzer M, von Gersdorff G, Böttinger EP, Lisanti MP (2001) Caveolin-1 regulates transforming growth factor (TGF)-β/SMAD signaling through an interaction with the TGF-β type I receptor. J Biol Chem 276:6727–6738PubMedGoogle Scholar
  89. 89.
    Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, Menne J, Lindschau C, Mende F, Luft FC, Schedl A, Haller H, Kurzchalia TV (2001) Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293:2449–2452PubMedGoogle Scholar
  90. 90.
    Sanz-Rodriguez F, Guerrero-Esteo M, Botella LM, Banville D, Vary CP, Bernabéu C (2004) Endoglin regulates cytoskeletal organization through binding to ZRP-1, a member of the Lim family of proteins. J Biol Chem 271:32858–32868Google Scholar
  91. 91.
    Conley BA, Koleva R, Smith JD, Kacer D, Zhang D, Bernabéu C, Vary CP (2004) Endoglin controls cell migration and composition of focal adhesions: function of the cytosolic domain. J Biol Chem 279:27440–27449PubMedGoogle Scholar
  92. 92.
    Lee NY, Blobe GC (2007) The interaction of endoglin with beta-arrestin2 regulates transforming growth factor-β-mediated ERK activation and migration in endothelial cells. J Biol Chem 282:21507–21517PubMedGoogle Scholar
  93. 93.
    Meng Q, Lux A, Holloschi A, Li J, Hughes JM, Foerg T, McCarthy JE, Heagerty AM, Kioschis P, Hafner M, Garland JM (2006) Identification of Tctex2β, a novel dynein light chain family member that interacts with different transforming growth factor-β receptors. J Biol Chem 281:37069–37080PubMedGoogle Scholar
  94. 94.
    Torsney E, Charlton R, Parums D, Collis M, Arthur HM (2002) Inducible expression of human endoglin during inflammation and wound healing in vivo. Inflamm Res 51:464–470PubMedGoogle Scholar
  95. 95.
    Jonker L, Arthur HM (2002) Endoglin expression in early development is associated with vasculogenesis and angiogenesis. Mech Dev 110:193–196PubMedGoogle Scholar
  96. 96.
    Millan FA, Denhez F, Kondaiah P, Akhurst RJ (1991) Embryonic gene expression patterns of TGFβ1, β2 and β3 suggest different developmental functions in vivo. Development 111:131–143PubMedGoogle Scholar
  97. 97.
    Charng MJ, Frenkel PA, Lin Q, Yamada M, Schwartz RJ, Olson EN, Overbeek P, Schneider MD (1998) A constitutive mutation of ALK5 disrupts cardiac looping and morphogenesis in mice. Dev Biol 199:72–79PubMedGoogle Scholar
  98. 98.
    Hirschi KK, Rohovsky SA, D’Amore PA (1998) PDGF, TGF-β, and heterotypic cell-cell interactions mediate endothelial cell-induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate. J Cell Biol 141:805–814PubMedGoogle Scholar
  99. 99.
    Carvalho RL, Jonker L, Goumans MJ, Larsson J, Bouwman P, Karlsson S, ten Dijke P, Arthur HM, Mummery CL (2004) Defective paracrine signalling by TGFβ in yolk sac vasculature of endoglin mutant mice: a paradigm for hereditary haemorrhagic telangiectasia. Development 131:6237–6247PubMedGoogle Scholar
  100. 100.
    Abdalla SA, Letarte M (2006) Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet 43:97–110PubMedGoogle Scholar
  101. 101.
    Jerkic M, Rivas-Elena JV, Prieto M, Carrón R, Sanz-Rodríguez F, Pérez-Barriocanal F, Rodríguez-Barbero A, Bernabéu C, López-Novoa JM (2004) Endoglin regulates nitric oxide-dependent vasodilatation. FASEB J 18:609–611PubMedGoogle Scholar
  102. 102.
    Letteboer TG, Mager JJ, Snijder RJ, Koeleman BP, Lindhout D, Ploos van Amstel JK, Westermann CJ (2006) Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia. J Med Genet 43:371–377PubMedGoogle Scholar
  103. 103.
    Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, Mitchell G, Drouin E, Westermann CJ, Marchuk DA (2004) A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 363:852–859PubMedGoogle Scholar
  104. 104.
    Letarte M, McDonald ML, Li C, Kathirkamathamby K, Vera S, Pece-Barbara N, Kumar S (2005) Reduced endothelial secretion and plasma levels of transforming growth factor-β1 in patients with hereditary hemorrhagic telangiectasia type 1. Cardiovasc Res 68:155–164PubMedGoogle Scholar
  105. 105.
    Sibai B, Dekker G, Kupferminc M (2005) Pre-eclampsia. Lancet 365:785–799PubMedGoogle Scholar
  106. 106.
    Baxter JK, Weinstein L (2004) HELLP syndrome: the state of the art. Obstet Gynecol Surv 59:838–845PubMedGoogle Scholar
  107. 107.
    Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK (1989) Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol 161:1200–1204PubMedGoogle Scholar
  108. 108.
    Fisher SJ (2004) The placental problem: linking abnormal cytotrophoblast differentiation to the maternal symptoms of preeclampsia. Reprod Biol Endocrinol 2:53PubMedGoogle Scholar
  109. 109.
    Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA (2004) Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672–683PubMedGoogle Scholar
  110. 110.
    Cruz-Gonzalez I, Pabón P, Rodríguez-Barbero A, Martín-Moreiras J, Pericacho M, Sánchez PL, Ramirez V, Sánchez-Ledesma M, Martín-Herrero F, Jiménez-Candil J, Maree AO, Sánchez-Rodríguez A, Martín-Luengo C, López-Novoa JM (2008) Identification of serum endoglin as a novel prognostic marker after acute myocardial infarction. J Cell Mol Med (in press)Google Scholar
  111. 111.
    Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438:932–936PubMedGoogle Scholar
  112. 112.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342PubMedGoogle Scholar
  113. 113.
    Wikström P, Lissbrant IF, Stattin P, Egevad L, Bergh A (2002) Endoglin (CD105) is expressed on immature blood vessels and is a marker for survival in prostate cancer. Prostate 51:268–275PubMedGoogle Scholar
  114. 114.
    Beresford MJ, Harris AL, Ah-See M, Daley F, Padhani AR, Makris A (2006) The relationship of the neo-angiogenic marker, endoglin, with response to neoadjuvant chemotherapy in breast cancer. Br J Cancer 95:1683–1688PubMedGoogle Scholar
  115. 115.
    El-Gohary YM, Silverman JF, Olson PR, Liu YL, Cohen JK, Miller R, Saad RS (2007) Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in prostatic adenocarcinoma. Am J Clin Pathol 127:572–579PubMedGoogle Scholar
  116. 116.
    Brewer CA, Setterdahl JJ, Li MJ, Johnston JM, Mann JL, McAsey ME (2000) Endoglin expression as a measure of microvessel density in cervical cancer. Obstet Gynecol 96:224–228PubMedGoogle Scholar
  117. 117.
    Seon BK, Matsuno F, Haruta Y, Kondo M, Barcos M (1997) Long-lasting complete inhibition of human solid tumors in SCID mice by targeting endothelial cells of tumor vasculature with antihuman endoglin immunotoxin. Clin Cancer Res 3:1031–1044PubMedGoogle Scholar
  118. 118.
    Bredow S, Lewin M, Hofmann B, Marecos E, Weissleder R (2000) Imaging of tumour neovasculature by targeting the TGF-β binding receptor endoglin. Eur J Cancer 36:675–681PubMedGoogle Scholar
  119. 119.
    Fonsatti E, Altomonte M, Nicotra MR, Natali PG, Maio M (2003) Endoglin (CD105): a powerful therapeutic target on tumor-associated angiogenetic blood vessels. Oncogene 22:6557–6563PubMedGoogle Scholar
  120. 120.
    Duff SE, Li C, Garland JM, Kumar S (2003) CD105 is important for angiogenesis: evidence and potential applications. FASEB J 17:984–992PubMedGoogle Scholar
  121. 121.
    Maier JA, Delia D, Thorpe PE, Gasparini G (1997) In vitro inhibition of endothelial cell growth by the antiangiogenic drug AGM-1470 (TNP-470) and the anti-endoglin antibody TEC-11. Anticancer Drugs 8:238–244PubMedGoogle Scholar
  122. 122.
    Takahashi N, Haba A, Matsuno F, Seon BK (2001) Antiangiogenic therapy of established tumors in human skin/severe combined immunodeficiency mouse chimeras by anti-endoglin (CD105) monoclonal antibodies, and synergy between anti-endoglin antibody and cyclophosphamide. Cancer Res 61:7846–7754PubMedGoogle Scholar
  123. 123.
    Tan GH, Wei YQ, Tian L, Zhao X, Yang L, Li J, He QM, Wu Y, Wen YJ, Yi T, Ding ZY, Kan B, Mao YQ, Deng HX, Li HL, Zhou CH, Fu CH, Xiao F, Zhang XW (2004) Active immunotherapy of tumors with a recombinant xenogeneic endoglin as a model antigen. Eur J Immunol 34:2012–2021PubMedGoogle Scholar
  124. 124.
    Jiao JG, Li YN, Wang H, Liu Q, Cao JX, Bai RZ, Huang FY (2006) A plasmid DNA vaccine encoding the extracellular domain of porcine endoglin induces anti-tumour immune response against self-endoglin-related angiogenesis in two liver cancer models. Dig Liver Dis 38:578–587PubMedGoogle Scholar
  125. 125.
    Balza E, Castellani P, Zijlstra A, Neri D, Zardi L, Siri A (2001) Lack of specificity of endoglin expression for tumor blood vessels. Int J Cancer 94:579–585PubMedGoogle Scholar
  126. 126.
    Seon BK (2002) Expression of endoglin (CD105) in tumor blood vessels. Int J Cancer 99:310–311PubMedGoogle Scholar
  127. 127.
    Kano MR, Bae Y, Iwata C, Morishita Y, Yashiro M, Oka M, Fujii T, Komuro A, Kiyono K, Kaminishi M, Hirakawa K, Ouchi Y, Nishiyama N, Kataoka K, Miyazono K (2007) Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-β signaling. Proc Natl Acad Sci USA 104:3460–3465PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Peter ten Dijke
    • 1
  • Marie-José Goumans
    • 1
  • Evangelia Pardali
    • 1
  1. 1.Department of Molecular Cell BiologyLeiden University Medical CenterLeidenThe Netherlands

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