Sulindac metabolites decrease cerebrovascular malformations in CCM3-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, pharmacol...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2015-07, Vol.112 (27), p.8421-8426
Main Authors: Bravi, Luca, 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
Format: Article
Language:English
Subjects:
abnormal development
animal models
Animals
anti-inflammatory agents
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Apoptosis Regulatory Proteins
beta Catenin - genetics
beta Catenin - metabolism
beta-catenin
Biological Sciences
Cells
central nervous system
Central Nervous System Neoplasms - drug therapy
Central Nervous System Neoplasms - genetics
Central Nervous System Neoplasms - metabolism
cerebral cavernous malformation
disease course
disease models
Disease Models, Animal
endothelial cells
Endothelial Cells - metabolism
Gene Expression Regulation, Neoplastic - drug effects
genes
Hemangioma, Cavernous, Central Nervous System - drug therapy
Hemangioma, Cavernous, Central Nervous System - genetics
Hemangioma, Cavernous, Central Nervous System - metabolism
Immunohistochemistry
Intracellular Signaling Peptides and Proteins - deficiency
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
Medical treatment
metabolites
mice
Mice, Knockout
Nervous system
Pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Rodents
Signal Transduction - drug effects
Signal Transduction - genetics
sulfides
Sulindac - analogs & derivatives
Sulindac - pharmacology
sulindac metabolites
surgery
Transforming Growth Factor beta - metabolism
vascular pathology
β-catenin
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Summary: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.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1501352112