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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2016 (publ. 2015, arch)     Display Documents

ID: 717324.0, MPI für molekulare Biomedizin / Jahrbuch 2016 (publ. 2015, arch)
Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice
Authors:Bravi, L.; Rudini, N.; Cuttano, R.; Giampietro, C.; Maddaluno, L.; Ferrarini, L.; Adams, R. H.; Corada, M.; Boulday, G.; Tournier-Lasserve, E.; Dejana, E.; Lampugnani, M. G.
Date of Publication (YYYY-MM-DD):2015-07-07
Title of Journal:Proc Natl Acad Sci u S A
Issue / Number:27
Start Page:8421
End Page:8426
Review Status:Internal review
Audience:Not Specified
Abstract / Description: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 beta-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a beta-catenin-driven transcription program that leads to endothelial-to-mesenchymal transition. TGF-beta/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 beta-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.
Free Keywords:Animals; Anti-Inflammatory Agents, Non-Steroidal/pharmacology; Central Nervous System Neoplasms/*drug therapy/genetics/metabolism; Disease Models, Animal; Endothelial Cells/metabolism; Gene Expression Regulation, Neoplastic/drug effects; Hemangioma, Cavernous, Central Nervous System/*drug therapy/genetics/metabolism; Immunohistochemistry; Intracellular Signaling Peptides and Proteins/*deficiency/genetics/metabolism; Mice, Knockout; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction/drug effects/genetics; Sulindac/*analogs & derivatives/pharmacology; Transforming Growth Factor beta/metabolism; beta Catenin/genetics/metabolism; cerebral cavernous malformation; endothelial cells; sulindac metabolites; vascular pathology; beta-catenin
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, 20139 Milan, Italy; Department of Biosciences, University of Milan, 20136 Milan, Italy; Faculty of Medicine, University of Munster, D-48149 Munster, Germany; Institut National de la Sante et de la Recherche Medicale, UMR-S 740, 75010 Paris, France; Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, 20139 Milan, Italy; Department of Immunology, Genetics and Pathology, Uppsala University, 75185 Uppsala, Sweden; Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, 20139 Milan, Italy; Mario Negri Institute for Pharmacological Research, 20156 Milan, Italy
Identifiers:ISSN:1091-6490 (Electronic) 0027-8424 (Linking) %R 10.1... [ID No:1]
URL: [ID No:2]
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