ISSN 1214-0287 (on-line), ISSN 1214-021X (printed)
J Appl Biomed
Volume 8 (2010), No 3, p 169-177
DOI 10.2478/v10136-009-0020-x

Involvement of the TGF-beta superfamily signalling pathway in hereditary haemorrhagic telangiectasia

Carmelo Bernabeu, Francisco Javier Blanco, Carmen Langa, Eva Maria Garrido-Martin, Luisa Maria Botella

Address: Carmelo Bernabeu, Centro de Investigaciones Biologicas, Ramiro de Maeztu, 9, Madrid 28040, Spain
bernabeu.c@cib.csic.es

Received 23rd February 2010.
Revised 29th April 2010.
Published online 13th May 2010.

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SUMMARY
Hereditary haemorrhagic telangiectasia (HHT) is a vascular hereditary autosomic dominant disease associated with epistaxis, telangiectases, gastrointestinal haemorrhages and arteriovenous malformations in lung, liver and brain. It affects 1-2 in 10,000 people. There are at least three different genes mutated in HHT, ENG, ACVRL1 and MADH4 that encode endoglin, activin receptor-like kinase (ALK1) and Smad4 proteins, respectively. These proteins are involved in the transforming growth factor (TGF)-beta superfamily signalling pathway of vascular endothelial cells. Mutations in ENG (HHT1) and ACVRL1 (HHT2) account for more than 90% of all HHT mutations. In this article, we review the underlying molecular and cellular bases and the therapeutic approaches that have been addressed in our laboratory in recent years.

KEY WORDS
transforming growth factor; endothelial cells; hereditary haemorrhagic telangiectasia; endoglin; ALK1; Smad; anti-fibrinolytic agents; estrogens

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

Albinana V, Bernabeu-Herrero ME, Zarrabeitia R, Bernabeu C, Botella LM: Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): Effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells. Thromb Haemost 103:525-534, 2010.

Bellon T, Corbi A, Lastres P, Cales C, Cebrian M, Vera S, Cheifetz S, Massague J, Letarte M, Bernabeu C: Identification and expression of two forms of the human transforming growth factor-beta-binding protein endoglin with distinct cytoplasmic regions. Eur J Immunol 23:2340-2345, 1993.

Bernabeu C, Conley BA, Vary CP: Novel biochemical pathways of endoglin in vascular cell physiology. J Cell Biochem 102:1375-1388, 2007.

Bernabeu C, Lopez-Novoa JM, Quintanilla M: An emerging role of TGF-beta co-receptors in cancer. Biochem Biophys Acta 1792:954-973, 2009.

Blanco FJ, Santibanez JF, Guerrero-Esteo M, Langa C, Vary CP, Bernabeu C: Interaction and functional interplay between endoglin and ALK-1, two components of the endothelial transforming growth factor-beta receptor complex. J Cell Physiol 204:574-584, 2005.

Blanco FJ, Grande MT, Langa C, Oujo B, Velasco S, Rodriguez-Barbero A, Perez-Gomez E, Quintanilla M, Lopez-Novoa JM, Bernabeu C: S-endoglin expression is induced in senescent endothelial cells and contributes to vascular pathology. Circ Res 103:1383-1392, 2008.

Botella LM, Sanchez-Elsner T, Rius C, Corbi A, Bernabeu C: Identification of a critical Sp1 site within the endoglin promoter and its involvement in the transforming growth factor-beta stimulation. J Biol Chem 276:34486-3494, 2001.

Botella LM, Sanchez-Elsner T, Sanz-Rodriguez F, Kojima S, Shimada J, Guerrero-Esteo M, Cooreman MP, Ratziu V, Langa C, Vary CP, Ramirez JR, Friedman S et al.: Transcriptional activation of endoglin and transforming growth factor-beta signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury. Blood 100:4001-4010, 2002.

David L, Feige JJ, Bailly S: Emerging role of bone morphogenetic proteins in angiogenesis. Cytokine Growth Factor Rev 20:203-212, 2009.

Faughnan ME, Palda VA, Garcia-Tsao G, Geisthoff UW, McDonald J, Proctor DD, Spears J, Brown DH, Buscarini E, Chesnutt MS, Cottin V, Ganguly A, et al.: International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. J Med Genet published online June 23, 2009 doi:10.1136/jmg.2009.069013

Fernandez-L A, Sanz-Rodriguez F, Zarrabeitia R, Perez-Molino A, Hebbel RP, Nguyen J, Bernabeu C, Botella LM: Blood outgrowth endothelial cells from hereditary haemorrhagic telangiectasia patients reveal abnormalities compatible with vascular lesions. Cardiovasc Res 68:235-248, 2005.

Fernandez-L A, Garrido-Martin EM, Sanz-Rodriguez F, Ramirez JR, Morales-Angulo C, Zarrabeitia R, Perez-Molino A, Bernabeu C, Botella LM: Therapeutic action of tranexamic acid in hereditary haemorrhagic telangiectasia (HHT): regulation of ALK-1/endoglin pathway in endothelial cells. Thromb Haemost 97:254-262, 2007.

Fernandez-Ruiz E, St-Jacques S, Bellon T, Letarte M, Bernabeu C: Assignment of the human endoglin gene (END) to 9q34>qter. Cytogenet Cell Genet 64:204-207, 1993.

Fonsatti E, Nicolay HJ, Altomonte M, Covre A, Maio M: Targeting cancer vasculature via endoglin/cd105: a novel antibody-based diagnostic and therapeutic strategy in solid tumors. Cardiovasc Res 86:12-19, 2010.

Fontalba A, Fernandez-L A, Garcia-Alegria E, Albinana V, Garrido-Martin EM, Blanco FJ, Zarrabeitia R, Perez-Molino A, Bernabeu-Herrero ME, Ojeda ML, Fernandez-Luna JL, Bernabeu C et al.: Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia. BMC Med Genet 9:75, 2008.

Gallione C, Aylsworth AS, Beis J, Berk T, Bernhardt B, Clark RD, Clericuzio C, Danesino C, Drautz J, Fahl J, Fan Z, Faughnan ME et al.: Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. Am J Med Genet A. 152A:333-339, 2010.

Gordon KJ, Blobe GC: Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochim Biophys Acta 1782:197-228, 2008.

Gougos A, Letarte M: Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J Biol Chem 265:8361-8364, 1990.

Goumans MJ, Liu Z, ten Dijke P: TGF-beta signaling in vascular biology and dysfunction. Cell Res 19:116-127, 2009.

Govani FS, Shovlin CL: Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur J Hum Genet 17:860-871, 2009.

Guerrero-Esteo M, Sanchez-Elsner T, Letamendia A, Bernabeu C: Extracellular and cytoplasmic domains of endoglin interact with the transforming growth factor-beta receptors I and II. J Biol Chem 277:29197-29209, 2002.

Henry-Berger J, Mouzat K, Baron S, Bernabeu C, Marceau G, Saru JP, Sapin V, Lobaccaro JM, Caira F: Endoglin (CD105) expression is regulated by the liver X receptor alpha (NR1H3) in human trophoblast cell line JAR. Biol Reprod 78:968-975, 2008.

Jerkic M, Rivas-Elena JV, Santibanez JF, Prieto M, Rodriguez-Barbero A, Perez-Barriocanal F, Pericacho M, Arevalo M, Vary CP, Letarte M, Bernabeu C, Lopez-Novoa JM: Endoglin regulates cyclooxygenase-2 expression and activity. Circ Res 99:248-256, 2006.

Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ, Stenzel TT, Speer M, Pericak-Vance MA, Diamond A, Guttmacher AE, Jackson CE et al.: Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 13:189-195, 1996.

Jovine L, Darie CC, Litscher ES, Wassarman PM: Zona pellucida domain proteins. Annu Rev Biochem 74:83-114, 2005.

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

Li X, Yonenaga Y, Seki T: Shortened ALK1 regulatory fragment maintains a specific activity in arteries feeding ischemic tissues. Gene Ther 16:1034-1041, 2009.

Llorca O, Trujillo A, Blanco FJ, Bernabeu C: Structural model of human endoglin, a transmembrane receptor responsible for hereditary hemorrhagic telangiectasia. J Mol Biol 365:694-705, 2007.

Mannucci PM: Hemostatic drugs. N Engl J Med 339:245-253, 1998.

McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J, McCormick MK, Pericak-Vance MA et al.: Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 8:345-351, 1994.

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 24:4450-4461, 2005.

Perez-Gomez E, Villa-Morales M, Santos J, Fernandez-Piqueras J, Gamallo C, Dotor J, Bernabeu C, Quintanilla M: A role for endoglin as a suppressor of malignancy during mouse skin carcinogenesis. Cancer Res 67:10268-10277, 2007.

Pimanda JE, Chan WY, Wilson NK, Smith AM, Kinston S, Knezevic K, Janes ME, Landry JR, Kolb-Kokocinski A, Frampton J, Tannahill D, Ottersbach K et al.: Endoglin expression in blood and endothelium is differentially regulated by modular assembly of the Ets/Gata hemangioblast code. Blood 112:4512-4522, 2008.

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 32:291-297, 1989.

Rius C, Smith JD, Almendro N, Langa C, Botella LM, Marchuk DA, Vary CP, Bernabeu C: Cloning of the promoter region of human endoglin, the target gene for hereditary hemorrhagic telangiectasia type 1. Blood 92:4677-4690, 1998.

Sabba C, Gallitelli M, Palasciano G: Efficacy of unusually high doses of tranexamic acid for the treatment of epistaxis in hereditary hemorrhagic telangiectasia. N Engl J Med 345:926, 2001.

Sanchez-Elsner T, Botella LM, Velasco B, Langa C, Bernabeu C: Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways. J Biol Chem 277:43799-43808, 2002.

Santibanez JF, Letamendia A, Perez-Barriocanal F, Silvestri C, Saura M, Vary CP, Lopez-Novoa JM, Attisano L, Bernabeu C: Endoglin increases eNOS expression by modulating Smad2 protein levels and Smad2-dependent TGF-beta signaling. J Cell Physiol 210:456-468, 2007.

Santibanez JF, Blanco FJ, Garrido-Martin EM, Sanz-Rodriguez F, del Pozo MA, Bernabeu C: Caveolin-1 interacts and cooperates with the transforming growth factor-beta type I receptor ALK1 in endothelial caveolae. Cardiovasc Res 77:791-799, 2008.

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 279:32858-32868, 2004.

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 91:66-67, 2000.

Velasco S, Alvarez-Munoz P, Pericacho M, Dijke PT, Bernabeu C, Lopez-Novoa JM, Rodriguez-Barbero A: L- and S-endoglin differentially modulate TGFbeta1 signaling mediated by ALK1 and ALK5 in L6E9 myoblasts. J Cell Sci 121:913-919, 2008.

Wong VC, Chan PL, Bernabeu C, Law S, Wang LD, Li JL, Tsao SW, Srivastava G, Lung ML: Identification of an invasion and tumor-suppressing gene, Endoglin (ENG), silenced by both epigenetic inactivation and allelic loss in esophageal squamous cell carcinoma. Int J Cancer 123:2816-2823, 2008.

Zacharski LR, Dunbar SD, Newsom WA, Jr.: Hemostatic effects of tamoxifen in HHT. Thromb Haemost 85:371-372, 2001.
CITED

Morales E, Morales R, Gutierrez E, Rojas-Rivera J, Praga M. Raloxifene and Bevacizumab for severe complications of hereditary haemorrhagic telangiectasia in a haemodialysis patient. Clin Kidney J. 5: 608-609, 2012.

Finnson KW, Philip A. Endoglin in liver fibrosis. J Cell Commun Sign 6: 1-4, 2012.

Alt A, Miguel-Romero L, Donderis J, Aristorena M, Blanco FJ, Round A, Rubio V, Bernabeu C, Marina A. Structural and functional insights into endoglin ligand recognition and binding. Plos One. 7: e29948, 2012.

Ali BR, Ben-Rebeh I, John A, Akawi NA, Milhem RM, Al-Shehhi NA, Al-Ameri MM, Al-Shamisi SA, Al-Gazali L. Endoplasmic Reticulum Quality Control Is Involved in the Mechanism of Endoglin-Mediated Hereditary Haemorrhagic Telangiectasia. Plos One. 6: e26206, 2011.

De Ruyck K, Sabbe N, Oberije C, Vandecasteele K, Thas O, De Ruysscher D, Lambin P, Van Meerbeeck J, De Neve W, Thierens H. Development of a multicomponent prediction model for acute esophagitis in lung cancer patiants receiving chemoradiotherapy. Int J Radiat Oncol Biol Phys. 81: 537-544, 2011.

Albinana V, Sanz-Rodriguez F, Recio-Poveda L, Albinana V, Sanz-Rodriguez F, Recio-Poveda L, Bernabeu C, Botella LM. Immunosuppressor FK506 Increases Endoglin and Activin Receptor-Like Kinase 1 Expression and Modulates Transforming Growth Factor-beta 1 Signaling in Endothelial Cells. Mol Pharmacol. 79: 833-843, 2011.

Berger J. The age of biomedicine: current trends in traditional subjects. J Appl Biomed. 9: 57-61, 2011.

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