Sulindac metabolites decrease cerebrovascular malformations inCCM3-knockout mice

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 theCCM3gene. We report an early, cell-autonomous, Wnt-receptor–independent stimulation of β-catenin transcription activity inCCM3-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 endothelialCCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.