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EMBO Mol Med. 2016 Jan 1;8(1):6-24. doi: 10.15252/emmm.201505433.

KLF4 is a key determinant in the development and progression of cerebral cavernous malformations.

Author information

1
IFOM the FIRC Institute of Molecular Oncology, Milan, Italy.
2
IFOM the FIRC Institute of Molecular Oncology, Milan, Italy Department of Biosciences, University of Milan, Milan, Italy.
3
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.
4
IFOM the FIRC Institute of Molecular Oncology, Milan, Italy on leave of absence at Department of Biomedicine, University of Basel, Basel, Switzerland.
5
IFOM the FIRC Institute of Molecular Oncology, Milan, Italy on leave of absence at Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
6
Yale Cardiovascular Research Center, New Haven, CT, USA.
7
Department of Tissue Morphogenesis, Faculty of Medicine, Max Planck Institute for Molecular Biomedicine University of Münster, Münster, Germany.
8
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.
9
Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
10
IFOM the FIRC Institute of Molecular Oncology, Milan, Italy Mario Negri Institute of Pharmacological Research, Milan, Italy.
11
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.

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.

KEYWORDS:

CCM; EndMT; KLF4; TGFβ‐BMP; endothelial cells

Comment in

PMID:
26612856
PMCID:
PMC4718159
DOI:
10.15252/emmm.201505433
[Indexed for MEDLINE]
Free PMC Article

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