Journal
NATURE MEDICINE
Volume 16, Issue 4, Pages 420-U101Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2131
Keywords
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Funding
- Institut National de la Sante et de la Recherche Medicale
- Agence Nationale de la Recherche (Agence Nationale de la Recherche blanc, Neuroscience)
- Fondation pour la Recherche Medicale
- Fondation Bettencourt
- Association pour la Recherche sur le Cancer [3980]
- Netherlands Heart Foundation [2008B106]
- British Heart Foundation
- EU [QLG1-CT-2001-01032]
- Stichting Wetenschappelijk Onderzoek Rendu Osler
- Besluit subsidies investeringen kennisinfrastructuur
- HHT Foundation International
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Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder characterized by vascular malformations. Many affected individuals develop recurrent nosebleeds, which can severely affect their quality of life and are clinically difficult to treat. We report here that treatment with thalidomide reduced the severity and frequency of nosebleeds (epistaxis) in the majority of a small group of subjects with HHT tested. The blood hemoglobin levels of the treated individuals rose as a result of reduced hemorrhage and enhanced blood vessel stabilization. In mice heterozygous for a null mutation in the Eng gene (encoding endoglin), an experimental model of HHT, thalidomide treatment stimulated mural cell coverage and thus rescued vessel wall defects. Thalidomide treatment increased platelet-derived growth factor-B (PDGF-B) expression in endothelial cells and stimulated mural cell activation. The effects of thalidomide treatment were partially reversed by pharmacological or genetic interference with PDGF signaling from endothelial cells to pericytes. Biopsies of nasal epithelium from individuals with HHT treated or not with thalidomide showed that similar mechanisms may explain the effects of thalidomide treatment in humans. Our findings demonstrate the ability of thalidomide to induce vessel maturation, which may be useful as a therapeutic strategy for the treatment of vascular malformations.
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