Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): Effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells

Virginia Albiñana; Maria E. Bernabeu-Herrero; Roberto Zarrabeitia; Carmelo Bernabeu; Luisa M. Botella

doi:10.1160/TH09-07-0425

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2010; 103(03): 441-451
DOI: 10.1160/TH09-07-0425

Theme Issue Article

Schattauer GmbH

Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): Effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells

Virginia Albiñana

¹Centro de Investigaciones Biológicas, Spanish Research Council (CSIC), Madrid, Spain

²Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain

,

Maria E. Bernabeu-Herrero

¹Centro de Investigaciones Biológicas, Spanish Research Council (CSIC), Madrid, Spain

⁴Present address: Siemens S.A., Sector Healthcare, Getafe, Spain

,

Roberto Zarrabeitia

²Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain

³Spanish HHT Unit, Hospital de Sierrallana. Torrelavega, Santander, Spain

,

Carmelo Bernabeu

¹Centro de Investigaciones Biológicas, Spanish Research Council (CSIC), Madrid, Spain

²Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain

,

Luisa M. Botella

¹Centro de Investigaciones Biológicas, Spanish Research Council (CSIC), Madrid, Spain

²Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain

› Institutsangaben

Abstract

Summary

Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is an autosomal dominant vascular disease. The clinical manifestations are epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations. There are two predominant types of HHT caused by mutations in Endoglin (ENG) and activin receptor-like kinase 1 (ALK1) (ACVRL1) genes, HHT1 and HHT2, respectively. No cure for HHT has been found and there is a current need to find new effective drug treatments for the disease. Some patients show severe epistaxis which interferes with their quality of life. We report preliminary results obtained with Raloxifene to treat epistaxis in postmenopausal HHT women diagnosed with osteoporosis. We tried to unravel the molecular mechanisms involved in the therapeutic effects of raloxifene. ENG and ACVRL1 genes code for proteins involved in the transforming growth factor β pathway and it is widely accepted that haploinsufficiency is the origin for the pathogenicity of HHT. Therefore, identification of drugs able to increase the expression of those genes is essential to propose new therapies for HHT. In vitro results show that raloxifene increases the protein and mRNA expression of ENG and ALK1 in cultured endothelial cells. Raloxifene also stimulates the promoter activity of these genes, suggesting a transcriptional regulation of ENG and ALK1. Furthermore, Raloxifene improved endothelial cell functions like tubulogenesis and migration in agreement with the reported functional roles of Endoglin and ALK1. Our pilot study provides a further hint that oral administration of raloxifene may be beneficial for epistaxis treatment in HHT menopausal women. The molecular mechanisms of raloxifene involve counteracting the haploin-sufficiency of ENG and ALK1.

Keywords

HHT - Endoglin - ALK1 - epistaxis - raloxifene

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Referenzen

References
1 Shovlin CL, Letarte M. Hereditary haemorrhagic telangiectasia and pulmonary arteriovenus malformations: issues in clinical management and review of pathogenic mechanisms. Thorax 1999; 54: 714-729.
2 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: 31-39.
3 Jessurun GA, Kamphuis DJ, van der Zande FH. et al. 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: 193-198.
4 Fernandez-L A, Sanz-Rodriguez F, Zarrabeitia R. et al. Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia and expression analysis of Endoglin and ALK1. Hum Mutat 2006; 27: 295.
5 Fontalba A, Fernandez-L A, García-Alegria E. et al. Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia. BMC Med Genet 2008; 9: 75.
6 McAllister KA, Grogg KM, Johnson DW. et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 1994; 8: 345-351.
7 Johnson DW, Berg JN, Baldwin MA. et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996; 13: 189-195.
8 Marchuk DA, Gallione CJ, Morrison LA. et al. A locus for cerebral cavernous malformations maps to chromosome 7q in two families. Genomics 1995; 28: 311-314.
9 Cole SG, Begbie ME, Wallace GM. et al. A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5. J Med Genet 2005; 42: 577-582.
10 Bayrak-Toydemir P, McDonald J, Akarsu N. et al. A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7. Am J Med Genet 2006; 140: 2155-2162.
11 Abdalla SA, Letarte M. Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet 2006; 43: 97-110.
12 Plauchu H, de Chadarévian JP, Bideau A. et al. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet 1989; 32: 291-297.
13 Pérez del Molino A, Zarrabeitia R, Fernández A. Hereditary hemorrhagic telangiectasia. Med Clin 2005; 124: 583-587.
14 Morales-Angulo C, del Valle-Zapico A. Hereditary hemorrhagic telangiectasia. Otolaryngol Head Neck Surg 1998; 119: 293.
15 Fernandez-L A, Garrido-Martin EM, Sanz-Rodriguez F. et al. Therapeutic action of tranexamic acid in hereditary haemorrhagic telangiectasia (HHT): regulation of ALK-1/endoglin pathway in endothelial cells. Thromb Haemost 2007; 97: 254-262.
16 Morales-Angulo C, Pérez del Molino A, Zarrabeitia R. et al. Treatment of epistaxes in hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease) with tranexamic acid. Acta Otorrinolaringol Esp 2007; 58: 129-132.
17 Shovlin CL, Sulaiman NL, Govani FS. et al. Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): association with venous thromboembolism. Thromb Haemost 2007; 98: 1031-1039.
18 Ghosh K, Ghosh K. Hereditary haemorrhagic telangiectasia (HHT): negotiating between the Scylla of bleeding and Charybdis of thrombosis. Thromb Haemost 2008; 100: 162-164.
19 Zacharski LR, Dunbar SD, Newsom WA Jr. Haemostatic effects of Tamoxifen in HHT. Thromb Haemost 2001; 85: 371-372.
20 Mosca L, Grady D, Barrett-Connor E. et al. Effect of raloxifene on stroke and venous thromboembolism according to subgroups in postmenopausal women at increased risk of coronary heart disease. Stroke 2009; 40: 147-155.
21 Sadick H, Naim R, Oulmi J. et al. Plasma surgery and topical estriol: effects on the nasal mucosa and long-term results in patients with Osler’s disease. Otolaryngol Head Neck Surg 2003; 129: 233-238.
22 Ades EW, Candal FJ, Swerlick RA. et al. HMEC-1: establishment of an immortalized human microvascular endothelial cell line. J Invest Dermatol 1992; 99: 683-690.
23 Azevedo GD, Franco RF, Baggio MS. et al. Procoagulant state after raloxifene therapy in postmenopausal women. Fertil Steril 2005; 84: 1680-1684.
24 Botella LM, Sánchez-Elsner T, Rius C. et al. Identification of a critical Sp1 site within the endoglin promoter and its involvement in the transforming growth factor-beta stimulation. J Biol Chem 2001; 276: 34486-34494.
25 Rius C, Smith JD, Almendro N. et al. Cloning of the promoter region of human endoglin, the target gene for hereditary hemorrhagic telangiectasia type 1. Blood 1998; 92: 4677-4690.
26 Sánchez-Elsner T, Botella LM, Velasco B. et al. Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways. J Biol Chem 2002; 277: 43799-43808.
27 Henry-Berger J, Mouzat K, Baron S. et al. Endoglin (CD105) expression is regulated by the liver X receptor alpha (NR1H3) in human trophoblast cell line JAR. Biol Reprod 2008; 78: 968-975.
28 Botella LM, Sánchez-Elsner T, Sanz-Rodriguez F. 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 2002; 100: 4001-4010.
29 Martino S, Costantino J, McNabb M. et al. The role of selective estrogen receptor modulators in the prevention of breast cancer: comparison of the clinical trials. Oncologist 2004; 9: 116-125.
30 Barettino D, Vivanco Ruiz MM, Stunnenberg HG. Characterization of the ligand-dependent transactivation domain of thyroid hormone receptor. EMBO J 1994; 13: 3039-3049.
31 McDonnell DP, Clemm DL, Hermann T. et al. Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Mol Endocrinol 1995; 9: 659-669.
32 Yang NN, Venugopalan M, Hardikar S. et al. Identification of an estrogen response element activated by metabolites of 17beta-estradiol and raloxifene. Science 1996; 273: 1222-25.
33 Paech K, Webb P, Kuiper GG. et al. Differential ligand activation of estrogen receptors ERa and ERß at AP1 sites. Science 1997; 277: 1508-1510.
34 Webb P, Lopez GN, Uht RM. et al. Tamoxifen activation of the estrogen receptor/ AP-1 pathway: potential origin for the cell-specific estrogen-like effects of antiestrogens. Mol Endocrinol 1995; 9: 443-456.
35 Shang Y, Brown M. Molecular determinants for the tissue specificity of SERMs. Science 2002; 295: 2465-2468.
36 Scafonas A, Reszka AA, Kimmel DB. et al. Agonist-like SERM effects on ERalpha-mediated repression of MMP1 promoter activity predict in vivo effects on bone and uterus. J Steroid Biochem Mol Biol 2008; 110: 197-206.
37 Catalano S, Rizza P, Gu G. et al. Fas ligand expression in TM4 Sertoli cells is enhanced by estradiol ″in situ″ production. J Cell Physiol 2007; 211: 448-456.
38 Hardman MJ, Emmerson E, Campbell L. et al. Selective estrogen receptor modulators accelerate cutaneous wound healing in ovariectomized female mice. Endocrinology 2008; 149: 551-557.
39 Li DY, Sorensen LK, Brooke BS. et al. Defective angiogenesis in mice lacking endoglin. Science 1999; 284: 1534-1537.
40 Fonsatti E, Altomonte M, Nicotra MR. et al. Endoglin (CD105): a powerful therapeutic target on tumor-associated angiogenetic blood vessels. Oncogene 2003; 22: 6557-6563.
41 Lebrin F, Deckers M, Bertolino P. et al. TGF-beta receptor function in the endothelium. Cardiovasc Res 2005; 65: 599-608.
42 Adomaityte J, Farooq M, Qayyum R. Effect of raloxifene therapy on venous thromboembolism in postmenopausal women: A meta-analysis. Thromb Haemost 2008; 99: 338-342.
43 Eilertsen AL, Liestøl S, Mowinckel MC. et al. Differential impact of conventional and low-dose oral hormone therapy (HT), tibolone and raloxifene on functionality of the activated protein C system. Thromb Haemost 2007; 97: 938-943.