title: 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 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.
authors.affiliation: IFOM the FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cuttano
authors.affiliation: IFOM the FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Noemi
authors.initials: N
authors.lastname: Rudini
authors.affiliation: IFOM the FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Bravi
authors.affiliation: IFOM the FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Corada
authors.affiliation: IFOM the FIRC Institute of Molecular Oncology, Milan, Italy Department of Biosciences, University of Milan, Milan, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Giampietro
authors.affiliation: IFOM the FIRC Institute of Molecular Oncology, Milan, Italy on leave of absence at Department of Neurology, Laboratory for Molecular Neuro-Oncology University Hospital Zurich, Zurich, Switzerland.
authors.forename: Eleanna
authors.initials: E
authors.lastname: Papa
authors.affiliation: IFOM the FIRC Institute of Molecular Oncology, Milan, Italy on leave of absence at Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Marco Francesco
authors.initials: MF
authors.lastname: Morini
authors.affiliation: IFOM the FIRC Institute of Molecular Oncology, Milan, Italy on leave of absence at Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Maddaluno
authors.affiliation: Yale Cardiovascular Research Center, New Haven, CT, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Baeyens
authors.affiliation: Department of Tissue Morphogenesis, Faculty of Medicine, Max Planck Institute for Molecular Biomedicine University of Münster, Münster, Germany.
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.affiliation: Case Cardiovascular Research Institute, Cleveland, OH, USA Harrington Heart & Vascular Institute, Cleveland, OH, USA Department of Medicine University Hospitals Case Medical Center, Cleveland, OH, USA Case Western Reserve University School of Medicine University Hospitals Case Medical Center, Cleveland, OH, USA.
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Owens
authors.affiliation: Yale Cardiovascular Research Center, New Haven, CT, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Schwartz
authors.affiliation: IFOM the FIRC Institute of Molecular Oncology, Milan, Italy Mario Negri Institute of Pharmacological Research, Milan, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Lampugnani
authors.affiliation: IFOM the FIRC Institute of Molecular Oncology, Milan, Italy Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden Department of Oncology and Oncohematology, University of Milan, Milan, Italy elisabetta.dejana@ifom.eu.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
mesh_terms: D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D000075927:KRIT1 Protein; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D055418:Bone Morphogenetic Protein 6; C000715467:KLF4 protein, human; D000075927:KRIT1 Protein; C000715468:Klf4 protein, mouse; C491535:Krit1 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D051898:Smad1 Protein; D016212:Transforming Growth Factor beta; D048054:Mitogen-Activated Protein Kinase 7
keywords: CCM; EndMT; KLF4; TGFβ‐BMP; endothelial cells