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

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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.

Rudini, NoemiIFOM, Milan, Italy. (författare)
Bravi, LucaIFOM, Milan, Italy. (författare)
Corada, MonicaIFOM, Milan, Italy. (författare)
Giampietro, CostanzaIFOM, Milan, Italy.;Univ Milan, Dept Biosci, Milan, Italy. (författare)
Papa, EleannaIFOM, Milan, Italy. (författare)
Morini, Marco FrancescoIFOM, Milan, Italy. (författare)
Maddaluno, LuigiIFOM, Milan, Italy. (författare)
Baeyens, NicolasYale Cardiovasc Res Ctr, New Haven, CT USA. (författare)
Adams, Ralf H.Univ Munster, Max Planck Inst Mol Biomed, Fac Med, Dept Tissue Morphogenesis, D-48149 Munster, Germany. (författare)
Jain, Mukesh K.Case Cardiovasc Res Inst, Cleveland, OH USA.;Harrington Heart & Vasc Inst, Cleveland, OH USA.;Univ Hosp Case Med Ctr, Dept Med, Cleveland, OH USA.;Case Western Reserve Univ, Sch Med, Univ Hosp Case Med Ctr, Cleveland, OH USA. (författare)
Owens, Gary K.Univ Virginia, Sch Med, Robert M Berne Cardiovasc Res Ctr, Charlottesville, VA 22908 USA. (författare)
Schwartz, MartinYale Cardiovasc Res Ctr, New Haven, CT USA. (författare)
Lampugnani, Maria GraziaIFOM, Milan, Italy.;Mario Negri Inst Pharmacol Res, Milan, Italy. (författare)
Dejana, ElisabettaUppsala universitet,Vaskulärbiologi,IFOM, Milan, Italy.;Univ Milan, Dept Oncol & Oncohematol, Milan, Italy.(Swepub:uu)elide443 (författare)
IFOM, Milan, Italy.IFOM, Milan, Italy.;Univ Milan, Dept Biosci, Milan, Italy. (creator_code:org_t)

Av författaren/redakt...: Cuttano, Roberto; Rudini, Noemi; Bravi, Luca; Corada, Monica; Giampietro, Cost ...; Papa, Eleanna; visa fler...; Morini, Marco Fr ...; Maddaluno, Luigi; Baeyens, Nicolas; Adams, Ralf H.; Jain, Mukesh K.; Owens, Gary K.; Schwartz, Martin; Lampugnani, Mari ...; Dejana, Elisabet ...; visa färre...

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