Clinically documented hemorrhage in cerebral arteriovenous malformations: MR characteristics.

Chappell, Phylliss M.; Steinberg, Gary K.; Marks, Michael P.

doi:10.1148/radiology.183.3.1584926

Cited by 20 publications

(6 citation statements)

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“…Those who harbor these vascular lesions are subject to an unpredictable risk of hemorrhage for which no pharmacologic therapy currently exists3. Even prior to overt hemorrhage, all lesions are surrounded by hemosiderin, the iron-laden deposits that result from extravascular blood that can be sensitively detected by MRI4 and suggest abnormal endothelial barrier function5. Although lesions have been described in a variety of vascular beds6, clinical manifestations are most common in the CNS, where the consequences of leak and hemorrhage can be stroke, seizure, or even death.…”

Section: Introductionmentioning

confidence: 99%

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

Whitehead¹,

Chan

Navankasattusas

et al. 2009

Nat Med

348

477

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SUMMARYCerebral cavernous malformation (CCM) is a common vascular dysplasia that affects both systemic and CNS blood vessels. Loss of function mutations in the CCM2 gene cause CCM. Here we show that targeted disruption of Ccm2 in mice results in failed lumen formation and early embryonic death through an endothelial cell autonomous mechanism. We demonstrate that CCM2 regulates endothelial cytoskeletal architecture, cell-cell interactions and lumen formation. Heterozygosity at Ccm2, a genotype equivalent to human CCM, results in impaired endothelial barrier function. Because our biochemical studies indicate that loss of CCM2 results in activation of RHOA GTPase, we rescued the cellular phenotype and barrier function in heterozygous mice using simvastatin, a drug known to inhibit Rho GTPases. These data offer the prospect for pharmacologic treatment of a human vascular dysplasia using a widely available and safe drug.

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Section: Introductionmentioning

confidence: 99%

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

Whitehead¹,

Chan

Navankasattusas

et al. 2009

Nat Med

348

477

View full text Add to dashboard Cite

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“…CCMs can lead to focal neurological deficits, seizures, and hemorrhagic stroke, but no pharmacologic therapy currently exists (3). CCMs predominantly occur in the central nervous system and are characterized by subclinical bleeding and consequential hemosiderin deposits that are detected by MRI (4). MRI is the primary clinical modality for detection, diagnosis, and management of CCMs.…”

Section: Introductionmentioning

confidence: 99%

Mutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice

Chan¹,

Drakos²,

Ruíz³

et al. 2011

J. Clin. Invest.

127

153

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Cerebral cavernous malformations (CCMs) are a common type of vascular malformation in the brain that are a major cause of hemorrhagic stroke. This condition has been independently linked to 3 separate genes: Krev1 interaction trapped (KRIT1), Cerebral cavernous malformation 2 (CCM2), and Programmed cell death 10 (PDCD10). Despite the commonality in disease pathology caused by mutations in these 3 genes, we found that the loss of Pdcd10 results in significantly different developmental, cell biological, and signaling phenotypes from those seen in the absence of Ccm2 and Krit1. PDCD10 bound to germinal center kinase III (GCKIII) family members, a subset of serine-threonine kinases, and facilitated lumen formation by endothelial cells both in vivo and in vitro. These findings suggest that CCM may be a common tissue manifestation of distinct mechanistic pathways. Nevertheless, loss of heterozygosity (LOH) for either Pdcd10 or Ccm2 resulted in CCMs in mice. The murine phenotype induced by loss of either protein reproduced all of the key clinical features observed in human patients with CCM, as determined by direct comparison with genotype-specific human surgical specimens. These results suggest that CCM may be more effectively treated by directing therapies based on the underlying genetic mutation rather than treating the condition as a single clinical entity.

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“…1,17 Depending on the location of the affected vessel, this often leads to bleeding, causing seizures, the main clinical sign of CCMs, or other neurological deteriorations. 4,18 Currently, 2 types of CCMs can be distinguished: a familial form, which follows an autosomal dominant pattern of inheritance, and a sporadic form. 16 The familial form is caused by loss-offunction mutations in 3 known genes: 6,7,13,20 KRIT1 (also known as CCM1), CCM2 (also known as malcalvernin or osm 14 ), and PDCD10 (also known as CCM3).…”

mentioning

confidence: 99%

Upregulation of transmembrane endothelial junction proteins in human cerebral cavernous malformations

Burkhardt¹,

Schmidt²,

Schoenauer³

et al. 2010

FOC

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Object Cerebral cavernous malformations (CCMs) are among the most prevalent cerebrovascular malformations, and endothelial cells seem to play a major role in the disease. However, the underlying mechanisms, including endothelial intercellular communication, have not yet been fully elucidated. In this article, the authors focus on the endothelial junction proteins CD31, VE-cadherin, and occludin as important factors for functional cell-cell contacts known as vascular adhesion molecules and adherence and tight junctions. Methods Thirteen human CCM specimens and 6 control tissue specimens were cryopreserved and examined for the presence of VE-cadherin, occludin, and CD31 by immunofluorescence staining. Protein quantification was performed by triplicate measurements using western blot analysis. Results Immunofluorescent analyses of the CCM sections revealed a discontinuous pattern of dilated microvessels and capillaries as well as increased expression of occludin, VE-cadherin, and CD31 in the intima and in the enclosed parenchymal tissue compared with controls. Protein quantification confirmed these findings by showing upregulation of the levels of these proteins up to 2–6 times. Conclusions A protocol enabling the molecular and morphological examination of the intercellular contact proteins in human CCM was validated. The abnormal and discontinuous pattern in these endothelial cell–contact proteins compared with control tissue explains the loose intercellular junctions that are considered to be one of the causes of CCM-associated bleeding or transendothelial oozing of erythrocytes. Despite the small number of specimens, this study demonstrates for the first time a quantitative analysis of endothelial junction proteins in human CCM.

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Clinically documented hemorrhage in cerebral arteriovenous malformations: MR characteristics.

Cited by 20 publications

References 0 publications

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

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

Mutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice

Upregulation of transmembrane endothelial junction proteins in human cerebral cavernous malformations

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