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Lab Invest. 2019 Mar;99(3):319-330. doi: 10.1038/s41374-018-0030-y. Epub 2018 Jun 26.

Phenotypic characterization of murine models of cerebral cavernous malformations.

Author information

1
Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
2
Department of Pathology, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
3
Department of Medicine, University of California, San Diego, CA, USA.
4
Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.
5
Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC, USA.
6
Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA. iawad@uchicago.edu.

Abstract

Cerebral cavernous malformations (CCMs) are clusters of dilated capillaries that affect around 0.5% of the population. CCMs exist in two forms, sporadic and familial. Mutations in three documented genes, KRIT1(CCM1), CCM2, and PDCD10(CCM3), cause the autosomal dominant form of the disease, and somatic mutations in these same genes underlie lesion development in the brain. Murine models with constitutive or induced loss of respective genes have been applied to study disease pathobiology and therapeutic manipulations. We aimed to analyze the phenotypic characteristic of two main groups of models, the chronic heterozygous models with sensitizers promoting genetic instability, and the acute neonatal induced homozygous knockout model. Acute model mice harbored a higher lesion burden than chronic models, more localized in the hindbrain, and largely lacking iron deposition and inflammatory cell infiltrate. The chronic model mice showed a lower lesion burden localized throughout the brain, with significantly greater perilesional iron deposition, immune B- and T-cell infiltration, and less frequent junctional protein immunopositive endothelial cells. Lesional endothelial cells in both models expressed similar phosphorylated myosin light chain immunopositivity indicating Rho-associated protein kinase activity. These data suggest that acute models are better suited to study the initial formation of the lesion, while the chronic models better reflect lesion maturation, hemorrhage, and inflammatory response, relevant pathobiologic features of the human disease.

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