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Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia

Abstract

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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Figure 1: Thalidomide normalizes excessive vessel branching in the retina of Eng+/− mice and enhances pericyte/VSMC coverage.
Figure 2: Thalidomide mediates vessel coverage by regulating pericyte function.
Figure 3: Effects of thalidomide on pericytes.
Figure 4: Thalidomide normalizes vessel coverage defects in Eng+/− mice.
Figure 5: Schematic illustration of how thalidomide normalizes vascular malformations in HHT.

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Acknowledgements

We thank A. Nishiyama (University of Connecticut Stem Cell Institute) for providing NG2DsRedBAC mice. This work was supported by grants from Institut National de la Santé et de la Recherche Médicale, Agence Nationale de la Recherche (Agence Nationale de la Recherche blanc, Neuroscience), Fondation pour la Recherche Médicale, Fondation Bettencourt, Association pour la Recherche sur le Cancer (3980), the Netherlands Heart Foundation (2008B106), the British Heart Foundation, the EU (QLG1-CT-2001-01032), Stichting Wetenschappelijk Onderzoek Rendu Osler and the Besluit subsidies investeringen kennisinfrastructuur program 'Dutch Platform for Tissue Engineering' and HHT Foundation International.

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F.L. designed and performed experiments, interpreted results and wrote the paper; S.S. and S.M. performed real-time PCR, mouse retina and skin immunofluorescence experiments; K.R. performed FACS sorting and in vitro cell culture experiments, interpreted results and helped write the paper; C.F. and C.B. performed retina experiments; S.v.d.B. performed stem cell experiments; T.M. and B.L. performed three-dimensional fibrinogen gel culture experiments; J.-L.T. provided NG2DsRedBAC and Pdgfbret/+ mice; H.M.A. provided endoglin-knockout mice; C.J.J.W., F.D., J.J.M. and R.J.S. directed the clinical study, performed surgery, provided clinical samples and interpreted results; A.E. and C.L.M. designed experiments, interpreted results and wrote the paper.

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Correspondence to Franck Lebrin or Christine L Mummery.

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Lebrin, F., Srun, S., Raymond, K. et al. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med 16, 420–428 (2010). https://doi.org/10.1038/nm.2131

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