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.
|Titolo:||Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice|
|Parole Chiave:||cerebral cavernous malformation; endothelial cells; sulindac metabolites; vascular pathology; β-catenin|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Progetto:||Transcriptional regulation of endothelial blood brain barrier differentiation by Wnt signaling|
|Data di pubblicazione:||7-lug-2015|
|Digital Object Identifier (DOI):||10.1073/pnas.1501352112|
|Appare nelle tipologie:||01 - Articolo su periodico|