KLF4 is a key determinant in the development and progression of cerebral cavernous malformations
Abstract 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...
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| Format: | Article |
| Language: | English |
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Springer Nature
2015-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201505433 |
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| author | Roberto Cuttano Noemi Rudini Luca Bravi Monica Corada Costanza Giampietro Eleanna Papa Marco Francesco Morini Luigi Maddaluno Nicolas Baeyens Ralf H Adams Mukesh K Jain Gary K Owens Martin Schwartz Maria Grazia Lampugnani Elisabetta Dejana |
| author_facet | Roberto Cuttano Noemi Rudini Luca Bravi Monica Corada Costanza Giampietro Eleanna Papa Marco Francesco Morini Luigi Maddaluno Nicolas Baeyens Ralf H Adams Mukesh K Jain Gary K Owens Martin Schwartz Maria Grazia Lampugnani Elisabetta Dejana |
| author_sort | Roberto Cuttano |
| collection | DOAJ |
| description | Abstract 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 (TGFβ/BMP) signaling. However, the mechanism linking Ccm gene inactivation and TGFβ/BMP‐dependent EndMT remains undefined. Here, we report that Ccm1 ablation leads to the activation of a MEKK3‐MEK5‐ERK5‐MEF2 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 TGFβ/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. |
| format | Article |
| id | doaj-art-fa0b10e5b7fd47ec840cb8f12c906459 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2015-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-fa0b10e5b7fd47ec840cb8f12c9064592025-08-20T03:43:30ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-11-018162410.15252/emmm.201505433KLF4 is a key determinant in the development and progression of cerebral cavernous malformationsRoberto Cuttano0Noemi Rudini1Luca Bravi2Monica Corada3Costanza Giampietro4Eleanna Papa5Marco Francesco Morini6Luigi Maddaluno7Nicolas Baeyens8Ralf H Adams9Mukesh K Jain10Gary K Owens11Martin Schwartz12Maria Grazia Lampugnani13Elisabetta Dejana14IFOM, the FIRC Institute of Molecular OncologyIFOM, the FIRC Institute of Molecular OncologyIFOM, the FIRC Institute of Molecular OncologyIFOM, the FIRC Institute of Molecular OncologyIFOM, the FIRC Institute of Molecular OncologyIFOM, the FIRC Institute of Molecular OncologyIFOM, the FIRC Institute of Molecular OncologyIFOM, the FIRC Institute of Molecular OncologyYale Cardiovascular Research CenterDepartment of Tissue Morphogenesis, Faculty of Medicine, Max Planck Institute for Molecular Biomedicine, University of MünsterCase Cardiovascular Research InstituteRobert M. Berne Cardiovascular Research Center, University of Virginia School of MedicineYale Cardiovascular Research CenterIFOM, the FIRC Institute of Molecular OncologyIFOM, the FIRC Institute of Molecular OncologyAbstract 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 (TGFβ/BMP) signaling. However, the mechanism linking Ccm gene inactivation and TGFβ/BMP‐dependent EndMT remains undefined. Here, we report that Ccm1 ablation leads to the activation of a MEKK3‐MEK5‐ERK5‐MEF2 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 TGFβ/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.https://doi.org/10.15252/emmm.201505433CCMEndMTendothelial cellsKLF4TGFβ‐BMP |
| spellingShingle | Roberto Cuttano Noemi Rudini Luca Bravi Monica Corada Costanza Giampietro Eleanna Papa Marco Francesco Morini Luigi Maddaluno Nicolas Baeyens Ralf H Adams Mukesh K Jain Gary K Owens Martin Schwartz Maria Grazia Lampugnani Elisabetta Dejana KLF4 is a key determinant in the development and progression of cerebral cavernous malformations EMBO Molecular Medicine CCM EndMT endothelial cells KLF4 TGFβ‐BMP |
| title | KLF4 is a key determinant in the development and progression of cerebral cavernous malformations |
| title_full | KLF4 is a key determinant in the development and progression of cerebral cavernous malformations |
| title_fullStr | KLF4 is a key determinant in the development and progression of cerebral cavernous malformations |
| title_full_unstemmed | KLF4 is a key determinant in the development and progression of cerebral cavernous malformations |
| title_short | KLF4 is a key determinant in the development and progression of cerebral cavernous malformations |
| title_sort | klf4 is a key determinant in the development and progression of cerebral cavernous malformations |
| topic | CCM EndMT endothelial cells KLF4 TGFβ‐BMP |
| url | https://doi.org/10.15252/emmm.201505433 |
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