Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 27, Pages 8421-8426Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1501352112
Keywords
cerebral cavernous malformation; endothelial cells; beta-catenin; sulindac metabolites; vascular pathology
Categories
Funding
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [AIRC IG 14471]
- Special Program Molecular Clinical Oncology 5x1000
- Fondazione Cassa di Risparmio delle Provincie Lombarde (CARIPLO) [2012-0678]
- European Community [268870, 317250, Endostem-Health-2009-241440]
- Fondazione CARIPLO [2014-1038]
- FIRC [16617]
- European consortium European Research Area Network NEURON
- [TELETHON-GGP14149]
- Fondazione Telethon Funding Source: Custom
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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.
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