Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice.

Proceedings of the National Academy of Sciences of the United States of America 2015 Jul 07

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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 β-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a β-catenin-driven transcription program that leads to endothelial-to-mesenchymal transition. TGF-β/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 β-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.

Citation

Luca Bravi, Noemi Rudini, Roberto Cuttano, Costanza Giampietro, Luigi Maddaluno, Luca Ferrarini, Ralf H Adams, Monica Corada, Gwenola Boulday, Elizabeth Tournier-Lasserve, Elisabetta Dejana, Maria Grazia Lampugnani. Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice. Proceedings of the National Academy of Sciences of the United States of America. 2015 Jul 07;112(27):8421-6