First name
Roberto
Last name
Cuttano
Year of Study
Research Center
Thesis Title
KLF4 is a key determinant in the development and progression of Cerebral Cavernous Malformations
Thesis Abstract
Cerebral cavernous malformations (CCMs) are capillary-venous malformations located in
the central nervous system often resulting in cerebral hemorrhage. Pharmacological treatment is
needed, since current therapy is limited to neurosurgery. CCM affects up to 0.5% of the human
population and occurs in both sporadic and familial forms. Loss-of-function mutations in any of
three genes CCM1, CCM2 and CCM3 have been associated to familial CCM. Postnatal endothelialspecific
deletion of any of the three Ccm genes in mice results in the development of brain vascular
malformations that faithfully resemble human CCM lesions. Here we describe that CCM are
formed by endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition (EndMT).
Ccm1 deletion leads to activation of the MEKK3-MEK5-ERK5-MEF2 signaling cascade resulting
in a marked upregulation of the transcription factor Krüppel-like factor 4 (KLF4) in ECs in vivo.
KLF4 promotes an endogenous production of bone morphogenetic protein 6 (BMP6) in ECs that, in
turn, activates the transforming growth factor-β (TGF-β) and BMP signalling pathway. KLF4
transcriptional activity and KLF4-dependent TGF-β/BMP pathway activation are responsible for
the EndMT switch observed in the absence of Ccm1. Interestingly, using both a pharmacological
treatment to inhibit TGF-β/BMP pathway or a genetic approach based on endothelial-specific Ccm1
and Klf4 double knockout mice, we strongly reduce the development and progression of CCM
lesions. Importantly loss of Klf4 almost abolishes mouse mortality in endothelial Ccm1-ablated
mice. These data indicate that KLF4, TGF-β/BMP pathway and EndMT are crucial events for CCM
pathogenesis and unveil KLF4 as a key therapeutic target for CCM.
the central nervous system often resulting in cerebral hemorrhage. Pharmacological treatment is
needed, since current therapy is limited to neurosurgery. CCM affects up to 0.5% of the human
population and occurs in both sporadic and familial forms. Loss-of-function mutations in any of
three genes CCM1, CCM2 and CCM3 have been associated to familial CCM. Postnatal endothelialspecific
deletion of any of the three Ccm genes in mice results in the development of brain vascular
malformations that faithfully resemble human CCM lesions. Here we describe that CCM are
formed by endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition (EndMT).
Ccm1 deletion leads to activation of the MEKK3-MEK5-ERK5-MEF2 signaling cascade resulting
in a marked upregulation of the transcription factor Krüppel-like factor 4 (KLF4) in ECs in vivo.
KLF4 promotes an endogenous production of bone morphogenetic protein 6 (BMP6) in ECs that, in
turn, activates the transforming growth factor-β (TGF-β) and BMP signalling pathway. KLF4
transcriptional activity and KLF4-dependent TGF-β/BMP pathway activation are responsible for
the EndMT switch observed in the absence of Ccm1. Interestingly, using both a pharmacological
treatment to inhibit TGF-β/BMP pathway or a genetic approach based on endothelial-specific Ccm1
and Klf4 double knockout mice, we strongly reduce the development and progression of CCM
lesions. Importantly loss of Klf4 almost abolishes mouse mortality in endothelial Ccm1-ablated
mice. These data indicate that KLF4, TGF-β/BMP pathway and EndMT are crucial events for CCM
pathogenesis and unveil KLF4 as a key therapeutic target for CCM.
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