The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases

Whitehead, Kevin J.; Chan, Aubrey C.; Navankasattusas, Sutip; Koh, Wonshill; London, Nyall R.; Jing, Ling; Mayo, Anne H.; Drakos, Stavros G.; Marchuk, Douglas A.; Davis, George E.; Li, Dean Y.

doi:10.1038/nm.1911

Cited by 341 publications

(502 citation statements)

References 40 publications

(48 reference statements)

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“…This hyperpermeability is associated with RhoA kinase (ROCK) activation, and can be rescued by ROCK inhibition. 3,6,7 We also showed hyperpermeability to Evans blue dye in vivo in the brain and lungs of Ccm1 haploinsufficient mice, also rescued by ROCK inhibition. 3 The ROCK activity has been linked to increased CCM lesion burden in mice, and ROCK inhibition is being tested as a potential therapy to prevent CCM lesion development.…”

Section: Introductionmentioning

confidence: 60%

“…3,8,10 Statin medication was shown to reverse dermal hyperpermeability associated with heterozygous Ccm in mice. 6 Until the present study, it has not been determined whether vascular permeability measurements in the human brain could reflect the differences postulated mechanistically. Also, it is unknown whether differences in brain or CCM lesion permeability are associated with various aspects of clinical disease activity.…”

Section: Cerebral Cavernous Malformation As Vascular Permeability Dismentioning

confidence: 83%

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Vascular Permeability in Cerebral Cavernous Malformations

Mikati

Khanna

Zhang

et al. 2015

J Cereb Blood Flow Metab

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Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive familial CCM disease had greater WMF permeability compared to those with milder disease phenotype, but similar lesion permeability. Subjects receiving statin medications for routine cardiovascular indications had a trend of lower WMF, but not lesion, permeability. This is the first demonstration of brain vascular hyperpermeability in humans with an autosomal dominant disease, as predicted mechanistically. Brain permeability, more than lesion permeability, may serve as a biomarker of CCM disease activity, and help calibrate potential drug therapy.

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Section: Introductionmentioning

confidence: 60%

Section: Cerebral Cavernous Malformation As Vascular Permeability Dismentioning

confidence: 83%

Vascular Permeability in Cerebral Cavernous Malformations

Mikati

Khanna

Zhang

et al. 2015

J Cereb Blood Flow Metab

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“…Because we found that CCM1 loss-of-function also caused a loss of appropriate DELTA-NOTCH signaling, one could assume that the sprouting process must be highly disorganized with many additional capillary branches (22). Three studies have recently reported that CCM2 is essential for cardiovascular development and maintaining vascular integrity (28)(29)(30). Thus, it appears that the CCM proteins, which are not related but can form a complex (9), together keep adult endothelial cells quiescent.…”

Section: Discussionmentioning

confidence: 99%

Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling

Wüstehube

Bartol

Liebler

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

176

144

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Cerebral cavernous malformations (CCM) are frequent vascular abnormalities caused by mutations in one of the CCM genes. CCM1 (also known as KRIT1) stabilizes endothelial junctions and is essential for vascular morphogenesis in mouse embryos. However, cellular functions of CCM1 during the early steps of the CCM pathogenesis remain unknown. We show here that CCM1 represents an antiangiogenic protein to keep the human endothelium quiescent. CCM1 inhibits endothelial proliferation, apoptosis, migration, lumen formation, and sprouting angiogenesis in primary human endothelial cells. CCM1 strongly induces DLL4-NOTCH signaling, which promotes AKT phosphorylation but reduces phosphorylation of the mitogen-activated protein kinase ERK. Consistently, blocking of NOTCH activity alleviates CCM1 effects. ERK phosphorylation is increased in human CCM lesions. Transplantation of CCM1-silenced human endothelial cells into SCID mice recapitulates hallmarks of the CCM pathology and serves as a unique CCM model system. In this setting, the multikinase inhibitor Sorafenib can ameliorate loss of CCM1-induced excessive microvascular growth, reducing the microvessel density to levels of normal wild-type endothelial cells. Collectively, our data suggest that the origin of CCM lesions is caused by perturbed Notch signaling-induced excessive capillary sprouting, which can be therapeutically targeted.endothelial cells | vascular malformations | CCM | KRIT1

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“…11). Recent studies have implicated defective Rho signaling as one of the consequences of depletion (or overexpression) of the CCM1, CCM2, and CCM3 proteins (12)(13)(14). Further links between CCM3 and its kinase partners and cytoskeletal dynamics via the Golgi were also uncovered.…”

Section: Pp2amentioning

confidence: 99%

Structure-Function Analysis of Core STRIPAK Proteins

Kean

Ceccarelli

Goudreault

et al. 2011

Journal of Biological Chemistry

132

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We show that striatins and CCM3 regulate the Golgi localization of MST4 in an opposite manner. Consistent with a previously described function for MST4 and CCM3 in Golgi positioning, depletion of CCM3 or striatins affects Golgi polarization, also in an opposite manner. We propose that STRIPAK regulates the balance between MST4 localization at the Golgi and in the cytosol to control Golgi positioning.

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The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases

Cited by 341 publications

References 40 publications

Vascular Permeability in Cerebral Cavernous Malformations

Vascular Permeability in Cerebral Cavernous Malformations

Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling

Structure-Function Analysis of Core STRIPAK Proteins

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