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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2017 (publ. 2016, arch)     Display Documents



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ID: 732160.0, MPI für molekulare Biomedizin / Jahrbuch 2017 (publ. 2016, arch)
KLF4 is a key determinant in the development and progression of cerebral cavernous malformations
Authors:Cuttano, R.; Rudini, N.; Bravi, L.; Corada, M.; Giampietro, C.; Papa, E.; Morini, M. F.; Maddaluno, L.; Baeyens, N.; Adams, R. H.; Jain, M. K.; Owens, G. K.; Schwartz, M.; Lampugnani, M. G.; Dejana, E.
Date of Publication (YYYY-MM-DD):2016-01
Title of Journal:EMBO Mol Med
Volume:8
Issue / Number:1
Start Page:6
End Page:24
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Cerebral cavernous malformations (CCMs) are vascular malformations located within the central nervous system often resulting in cerebral hemorrhage. Pharmacological treatment is needed, since current therapy is limited to neurosurgery. Familial CCM is caused by loss-of-function mutations in any of Ccm1, Ccm2, and Ccm3 genes. CCM cavernomas are lined by endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition (EndMT). This switch in phenotype is due to the activation of the transforming growth factor beta/bone morphogenetic protein (TGFb/BMP) signaling. However, the mechanism linking Ccm gene inactivation and TGFb/ BMP-dependent EndMT remains undefined. Here, we report that Ccm1 ablation leads to the activation of a MEKK3-MEK5-ERK5MEF2 signaling axis that induces a strong increase in Kruppel-like factor 4 (KLF4) in ECs in vivo. KLF4 transcriptional activity is responsible for the EndMT occurring in CCM1-null ECs. KLF4 promotes TGFb/BMP signaling through the production of BMP6. Importantly, in endothelial-specific Ccm1 and Klf4 double knockout mice, we observe a strong reduction in the development of CCM and mouse mortality. Our data unveil KLF4 as a therapeutic target for CCM.
Free Keywords:CCM; EndMT; endothelial cells; KLF4; TGF beta-BMP; blood-brain-barrier; endothelial-mesenchymal transition; kruppel-like; factors; transcription factor; ve-cadherin; growth-factor; vascular; integrity; signaling pathway; shear-stress; rho kinase; Research & Experimental Medicine
External Publication Status:published
Document Type:Article
Communicated by:Jeanine Müller-Keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Dejana, E (reprint author), IFOM, Milan, Italy. elisabetta.dejana@ifom.eu %G English
Identifiers:ISSN:1757-4676 [ID No:1]
URL:<Go to ISI>://WOS:000368135800003 [ID No:2]
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