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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 6 / antagonists & inhibitors
  • Bone Morphogenetic Protein 6 / genetics
  • Bone Morphogenetic Protein 6 / metabolism
  • Cell Proliferation
  • Disease Models, Animal
  • Disease Progression
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • HEK293 Cells
  • Hemangioma, Cavernous, Central Nervous System / genetics*
  • Hemangioma, Cavernous, Central Nervous System / metabolism
  • Hemangioma, Cavernous, Central Nervous System / pathology*
  • Humans
  • KRIT1 Protein
  • Kruppel-Like Transcription Factors / antagonists & inhibitors
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microtubule-Associated Proteins / antagonists & inhibitors
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mitogen-Activated Protein Kinase 7 / metabolism
  • Mutation
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA Interference
  • Signal Transduction
  • Smad1 Protein / metabolism
  • Transforming Growth Factor beta / metabolism

Substances

  • Bone Morphogenetic Protein 6
  • GKLF protein
  • KRIT1 Protein
  • Krit1 protein, mouse
  • Kruppel-Like Transcription Factors
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins
  • Smad1 Protein
  • Transforming Growth Factor beta
  • Mitogen-Activated Protein Kinase 7