Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): Effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells.
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 beta 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 haploinsufficiency of ENG and ALK1.
Centro de Investigaciones Biológicas, Spanish Research Council (CSIC), Madrid, Spain.
Virginia
V
Albiñana
Maria E
ME
Bernabeu-Herrero
Roberto
R
Zarrabeitia
Carmelo
C
Bernabéu
Luisa M
LM
Botella
D030301:Activin Receptors, Type II / Q000187:drug effects* / Q000235:genetics; D000368:Aged; D015703:Antigens, CD / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D000071063:Endoglin; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D004844:Epistaxis / Q000188:drug therapy; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008593:Menopause; D008875:Middle Aged; D011446:Prospective Studies; D020849:Raloxifene Hydrochloride / Q000494:pharmacology* / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000235:genetics; D020845:Selective Estrogen Receptor Modulators; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000188:drug therapy*; D014158:Transcription, Genetic / Q000187:drug effects
D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D004967:Estrogens; D011956:Receptors, Cell Surface; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II