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.