Phenotypic characterization of murine models of cerebral cavernous malformations.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Zeineddine, HA; Girard, R; Saadat, L; Shen, L; Lightle, R; Moore, T; Cao, Y; Hobson, N; Shenkar, R; Avner, K; Chaudager, K; Koskimäki, J; Polster, SP; Fam, MD; Shi, C; Lopez-Ramirez, MA; Tang, AT; Gallione, C; Kahn, ML; Ginsberg, M; Marchuk, DA; Awad, IA

Published Date

  • March 2019

Published In

Volume / Issue

  • 99 / 3

Start / End Page

  • 319 - 330

PubMed ID

  • 29946133

Pubmed Central ID

  • PMC6309944

Electronic International Standard Serial Number (EISSN)

  • 1530-0307

Digital Object Identifier (DOI)

  • 10.1038/s41374-018-0030-y


  • eng

Conference Location

  • United States