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

Nature Medicine volume 16, pages 420–428 (2010)Cite this article

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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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References

  1. McAllister, K.A. et al. Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat. Genet. 8, 345–351 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Johnson, D.W. et al. Mutations in the activin receptor–like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat. Genet. 13, 189–195 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Lebrin, F., Deckers, M., Bertolino, P. & Ten Dijke, P. TGF-β receptor function in the endothelium. Cardiovasc. Res. 65, 599–608 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Lebrin, F. & Mummery, C.L. Endoglin-mediated vascular remodeling: mechanisms underlying hereditary hemorrhagic telangiectasia. Trends Cardiovasc. Med. 18, 25–32 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Govani, F.S. & Shovlin, C.L. Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur. J. Hum. Genet. 17, 860–871 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cirulli, A. et al. Vascular endothelial growth factor serum levels are elevated in patients with hereditary hemorrhagic telangiectasia. Acta Haematol. 110, 29–32 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Letarte, M. et al. Reduced endothelial secretion and plasma levels of transforming growth factor-β1 in patients with hereditary hemorrhagic telangiectasia type 1. Cardiovasc. Res. 68, 155–164 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Carvalho, R.L. et al. Defective paracrine signalling by TGFβ in yolk sac vasculature of endoglin mutant mice: a paradigm for hereditary haemorrhagic telangiectasia. Development 131, 6237–6247 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. ten Dijke, P. & Arthur, H.M. Extracellular control of TGFβ signalling in vascular development and disease. Nat. Rev. Mol. Cell Biol. 8, 857–869 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Bauditz, J. & Lochs, H. Angiogenesis and vascular malformations: antiangiogenic drugs for treatment of gastrointestinal bleeding. World J. Gastroenterol. 13, 5979–5984 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kabbinavar, F. et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J. Clin. Oncol. 21, 60–65 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Bose, P., Holter, J.L. & Selby, G.B. Bevacizumab in hereditary hemorrhagic telangiectasia. N. Engl. J. Med. 360, 2143–2144 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. D'Amato, R.J., Loughnan, M.S., Flynn, E. & Folkman, J. Thalidomide is an inhibitor of angiogenesis. Proc. Natl. Acad. Sci. USA 91, 4082–4085 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Therapontos, C., Erskine, L., Gardner, E.R., Figg, W.D. & Vargesson, N. Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation. Proc. Natl. Acad. Sci. USA 106, 8573–8578 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bauditz, J., Schachschal, G., Wedel, S. & Lochs, H. Thalidomide for treatment of severe intestinal bleeding. Gut 53, 609–612 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dabak, V., Kuriakose, P., Kamboj, G. & Shurafa, M. A pilot study of thalidomide in recurrent GI bleeding due to angiodysplasias. Dig. Dis. Sci. 53, 1632–1635 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Kamalaporn, P. et al. Thalidomide for the treatment of chronic gastrointestinal bleeding from angiodysplasias: a case series. Eur. J. Gastroenterol. Hepatol. 21, 1347–1350 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Kurstin, R. Using thalidomide in a patient with epithelioid leiomyosarcoma and Osler-Weber-Rendu disease. Oncology (Williston Park) 16, 21–24 (2002).

    PubMed  Google Scholar 

  19. Pérez-Encinas, M., Rabunal Martinez, M.J. & Bello Lopez, J.L. Is thalidomide effective for the treatment of gastrointestinal bleeding in hereditary hemorrhagic telangiectasia? Haematologica 87, ELT34 (2002).

    PubMed  Google Scholar 

  20. Melchert, M. & List, A. The thalidomide saga. Int. J. Biochem. Cell Biol. 39, 1489–1499 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Jakobsson, L., Kreuger, J. & Claesson-Welsh, L. Building blood vessels-stem cell models in vascular biology. J. Cell Biol. 177, 751–755 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Torsney, E. et al. Mouse model for hereditary hemorrhagic telangiectasia has a generalized vascular abnormality. Circulation 107, 1653–1657 (2003).

    Article  PubMed  Google Scholar 

  23. Bourdeau, A., Dumont, D.J. & Letarte, M. A murine model of hereditary hemorrhagic telangiectasia. J. Clin. Invest. 104, 1343–1351 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fruttiger, M. Development of the retinal vasculature. Angiogenesis 10, 77–88 (2007).

    Article  PubMed  Google Scholar 

  25. Zhu, X., Bergles, D.E. & Nishiyama, A. NG2 cells generate both oligodendrocytes and gray matter astrocytes. Development 135, 145–157 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Lindahl, P., Johansson, B.R., Leveen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B–deficient mice. Science 277, 242–245 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Hellström, M., Kalen, M., Lindahl, P., Abramsson, A. & Betsholtz, C. Role of PDGF-B and PDGFR-β in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126, 3047–3055 (1999).

    PubMed  Google Scholar 

  28. Hellström, M. et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153, 543–553 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Enge, M. et al. Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy. EMBO J. 21, 4307–4316 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lindblom, P. et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 17, 1835–1840 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dudley, A. et al. STI-571 inhibits in vitro angiogenesis. Biochem. Biophys. Res. Commun. 310, 135–142 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Hasumi, Y. et al. Identification of a subset of pericytes that respond to combination therapy targeting PDGF and VEGF signaling. Int. J. Cancer 121, 2606–2614 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Vollmar, B., Morgenthaler, M., Amon, M. & Menger, M.D. Skin microvascular adaptations during maturation and aging of hairless mice. Am. J. Physiol. Heart Circ. Physiol. 279, H1591–H1599 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Gaengel, K., Genove, G., Armulik, A. & Betsholtz, C. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler. Thromb. Vasc. Biol. 29, 630–638 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Orlidge, A. & D′Amore, P.A. Inhibition of capillary endothelial cell growth by pericytes and smooth muscle cells. J. Cell Biol. 105, 1455–1462 (1987).

    Article  CAS  PubMed  Google Scholar 

  36. Sato, Y. & Rifkin, D.B. Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor-β 1–like molecule by plasmin during co-culture. J. Cell Biol. 109, 309–315 (1989).

    Article  CAS  PubMed  Google Scholar 

  37. Hamzah, J. et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453, 410–414 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Bajanca, F., Luz, M., Duxson, M.J. & Thorsteinsdottir, S. Integrins in the mouse myotome: developmental changes and differences between the epaxial and hypaxial lineage. Dev. Dyn. 231, 402–415 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Arthur, H.M. et al. Endoglin, an ancillary TGFβ receptor, is required for extraembryonic angiogenesis and plays a key role in heart development. Dev. Biol. 217, 42–53 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Uutela, M. et al. PDGF-D induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis. Blood 104, 3198–3204 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Gerhardt, H. et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J. Cell Biol. 161, 1163–1177 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hellström, M. et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445, 776–780 (2007).

    Article  PubMed  Google Scholar 

Download references

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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Author notes

  1. Anne Eichmann and Christine L Mummery: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale U833, Collège de France, Paris, France

    Franck Lebrin, Samly Srun, Sabrina Martin, Catarina Freitas, Christiane Bréant, Thomas Mathivet, Bruno Larrivée & Anne Eichmann

  2. Institut Curie, Centre de Recherche, Centre National de la Recherche Scientifique UMR144, Paris, France

    Karine Raymond

  3. Hubrecht Institute, Developmental Biology and Stem Cell Research, Utrecht, The Netherlands

    Stieneke van den Brink

  4. Institut National de la Santé et de la Recherche Médicale U711, Paris, France

    Jean-Léon Thomas

  5. Institute of Human Genetics, International Centre for Life, Newcastle University, Newcastle, UK

    Helen M Arthur

  6. St. Antonius Hospital, Nieuwegein, The Netherlands

    Cornelis J J Westermann, Frans Disch, Johannes J Mager & Repke J Snijder

  7. Department of Anatomy and Embryology, Leiden University Medical Centre, Leiden, The Netherlands

    Christine L Mummery

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Contributions

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.

Corresponding authors

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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