Lack of CCM1 induces hypersprouting and impairs response to flow

Mleynek, Tara; Chan, Aubrey C.; Redd, Michael J.; Gibson, Christopher C.; Davis, Chadwick T.; Shi, Dallas; Chen, Tiehua; Carter, Kandis L.; Jing, Ling; Gerhardt, Holger; Whitehead, Kevin J.; Li, Dean Y.

doi:10.1093/hmg/ddu342

Cited by 32 publications

(41 citation statements)

References 22 publications

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“…Nfatc1 Cre (Wu et al, 2012), Ccm2 fl/fl (Zheng et al, 2012), Pdcd10 fl/fl (Chan et al, 2010) and Krit1 fl/fl (Mleynek et al, 2014) animals have been previously described. The ROSA26-YFP reporter line was obtained from Jackson Laboratories (#006148).…”

Section: Methodsmentioning

confidence: 99%

The Cerebral Cavernous Malformation Pathway Controls Cardiac Development via Regulation of Endocardial MEKK3 Signaling and KLF Expression

et al. 2015

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SUMMARY The cerebral cavernous malformation (CCM) pathway is required in endothelial cells for normal cardiovascular development and to prevent postnatal vascular malformations, but its molecular effectors are not well defined. Here we show that loss of CCM signaling in endocardial cells results in mid-gestation heart failure associated with premature degradation of cardiac jelly. CCM deficiency dramatically alters endocardial and endothelial gene expression, including increased expression of the Klf2 and Klf4 transcription factors and the Adamts4 and Adamts5 proteases that degrade cardiac jelly. These changes in gene expression result from increased activity of MEKK3, a mitogen-activated protein kinase that binds CCM2 in endothelial cells. MEKK3 is both necessary and sufficient for expression of these genes, and partial loss of MEKK3 rescues cardiac defects in CCM-deficient embryos. These findings reveal a molecular mechanism by which CCM signaling controls endothelial gene expression during cardiovascular development that may also underlie CCM formation.

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Section: Methodsmentioning

confidence: 99%

The Cerebral Cavernous Malformation Pathway Controls Cardiac Development via Regulation of Endocardial MEKK3 Signaling and KLF Expression

et al. 2015

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“…Mice with a conditional (floxed) allele for Krit1, a germline deleted Krit1 allele and the endothelial inducible Cre recombinase (PDGFB-iCreER T2 ) have been described. 5,15 Cre recombinase activity was induced by administration of a single injection of tamoxifen and PDGFB-iCreER T2 ; Krit1 flox/+ littermate controls, were injected ip with 3 mg/kg SU5416 dissolved in corn oil (TOCRIS/R&D), or vehicle (corn oil), twice weekly, starting at P14. Treatment continued until the mice were four months of age, at which time the animals were sacrificed and perfused via the right ventricle with PBS, followed by perfusion of 3.7% formaldehyde to fix the tissue.…”

Section: Mouse Modelsmentioning

confidence: 99%

“…To test this directly, we utilized Krit1 ieKO mice, which develop lesions similar to those seen in human CCM patients. 15 Tamoxifen injection of PDGFB-iCreER T2 Krit1 flox/ flox mice at P1 stimulates endothelial-specific Cre-mediated recombination and loss of Krit1 protein in >90% of the endothelium. In these animals, Type 1 lesions (enlarged vessels with a single lumen but no apparent haemorrhage) are visible to the naked eye in >90% of animals at 2 weeks of age ( Figure S1).…”

Section: Vegfr2 Inhibition Reduces Lesion Number In Krit1 Endothelimentioning

confidence: 99%

VEGF signalling enhances lesion burden in KRIT1 deficient mice

DiStefano

Glading

2019

J Cellular Molecular Medi

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The exact molecular mechanisms underlying CCM pathogenesis remain a complicated and controversial topic. Our previous work illustrated an important VEGF signalling loop in KRIT1 depleted endothelial cells. As VEGF is a major mediator of many vascular pathologies, we asked whether the increased VEGF signalling downstream of KRIT1 depletion was involved in CCM formation. Using an inducible KRIT1 endothelial‐specific knockout mouse that models CCM, we show that VEGFR2 activation plays a role in CCM pathogenesis in mice. Inhibition of VEGFR2 using a specific inhibitor, SU5416, significantly decreased the number of lesions formed and slightly lowered the average lesion size. Notably, VEGFR2 inhibition also decreased the appearance of lesion haemorrhage as denoted by the presence of free iron in adjacent tissues. The presence of free iron correlated with increased microvessel permeability in both skeletal muscle and brain, which was completely reversed by SU5416 treatment. Finally, we show that VEGFR2 activation is a common downstream consequence of KRIT1, CCM2 and CCM3 loss of function, though the mechanism by which VEGFR2 activation occurs likely varies. Thus, our study clearly shows that VEGFR2 activation downstream of KRIT1 depletion enhances the severity of CCM formation in mice, and suggests that targeting VEGF signalling may be a potential future therapy for CCM.

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“…Similarly to patients, in murine models the vascular phenotype can be faithfully reproduced by endothelium-specific loss-of-function mutations of anyone of these three Ccm genes (Liebner et al, 2008;Boulday et al, 2011;Chan et al, 2011;McDonald et al, 2011;Maddaluno et al, 2013;Mleynek et al, 2014). CCM tripartite cytoplasmic complex controls barrier functions both by inhibiting the small GTPase RhoA (Whitehead et al, 2009;Borikova et al, 2010;Stockton et al, 2010) and by acting as an effector of the small GTPase Ras-related protein 1 (Rap1) at the cell-to-cell adherens junctions (AJ) in the endothelium (Beraud-Dufour et al, 2007;Glading et al, 2007;Glading & Ginsberg, 2010;Fisher & Boggon, 2013).…”

Section: Introductionmentioning

confidence: 99%

KLF 4 is a key determinant in the development and progression of cerebral cavernous malformations

et al. 2015

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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 (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.

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Lack of CCM1 induces hypersprouting and impairs response to flow

Cited by 32 publications

References 22 publications

The Cerebral Cavernous Malformation Pathway Controls Cardiac Development via Regulation of Endocardial MEKK3 Signaling and KLF Expression

The Cerebral Cavernous Malformation Pathway Controls Cardiac Development via Regulation of Endocardial MEKK3 Signaling and KLF Expression

VEGF signalling enhances lesion burden in KRIT1 deficient mice

KLF 4 is a key determinant in the development and progression of cerebral cavernous malformations

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