Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice
2015 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 27, 8421-8426 p.Article in journal (Refereed) Published
Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell-selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor-independent stimulation of beta-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a beta-catenin-driven transcription program that leads to endothelial-tomesenchymal transition. TGF-beta/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate beta-catenin transcription activity, reduce vascular malformations in endothelial CCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.
Place, publisher, year, edition, pages
2015. Vol. 112, no 27, 8421-8426 p.
cerebral cavernous malformation, endothelial cells, beta-catenin, sulindac metabolites, vascular pathology
Other Medical Sciences not elsewhere specified
IdentifiersURN: urn:nbn:se:uu:diva-259652DOI: 10.1073/pnas.1501352112ISI: 000357527600075PubMedID: 26109568OAI: oai:DiVA.org:uu-259652DiVA: diva2:847535
This study was supported by grants (to E.D.) from TELETHON-GGP14149, Associazione Italiana per la Ricerca sul Cancro (AIRC) (AIRC IG 14471), "Special Program Molecular Clinical Oncology 5x1000" to AIRC-Gruppo Italiano Malattie Mieloproliferative, Fondazione Cassa di Risparmio delle Provincie Lombarde (CARIPLO) Contract 2012-0678, the European Community (Wnt for Brain Contract 268870; Innovative Training Networks Vessel 317250, Endostem-Health-2009-241440), and Fondazione CARIPLO Contract 2014-1038 (to N.R.). R.C. was supported by the FIRC fellowship 16617. Part of this work was funded by the European consortium European Research Area Network NEURON (to E.T.-L.).
Dejana E and Lampugnani MG share the last authorship and corresponding.2015-08-202015-08-102016-02-29