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. 2004 Nov;165(5):1509-18.
doi: 10.1016/S0002-9440(10)63409-8.

Loss of p53 Sensitizes Mice With a Mutation in Ccm1 (KRIT1) to Development of Cerebral Vascular Malformations

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Free PMC article

Loss of p53 Sensitizes Mice With a Mutation in Ccm1 (KRIT1) to Development of Cerebral Vascular Malformations

Nicholas W Plummer et al. Am J Pathol. .
Free PMC article

Abstract

Cerebral cavernous malformations (CCM) consist of clusters of abnormally dilated blood vessels. Hemorrhaging of these lesions can cause seizures and lethal stroke. Three loci are associated with autosomal dominant CCM, and the causative genes have been identified for CCM1 and CCM2. We have generated mice with a targeted mutation of the Ccm1 gene, but an initial survey of 20 heterozygous mice failed to detect any cavernous malformations. To test the hypothesis that growth of cavernous malformations depends on somatic loss of heterozygosity at the Ccm1 locus, we bred animals that were heterozygous for the Ccm1 mutation and homozygous for loss of the tumor suppressor Trp53 (p53), which has been shown to increase the rate of somatic mutation. We observed vascular lesions in the brains of 55% of the double-mutant animals but none in littermates with other genotypes. Although the genetic evidence suggested somatic mutation of the wild-type Ccm1 allele, we were unable to demonstrate loss of heterozygosity by molecular methods. An alternative explanation is that p53 plays a direct role in formation of the vascular malformations. The striking similarity of the human and mouse lesions indicates that the Ccm1(+/-) Trp53(-/-) mice are an appropriate animal model of CCM.

Figures

Figure 1
Figure 1
General appearance of vascular malformations in Ccm1+/− Trp53−/− mice. The mouse lesions consist of grossly dilated, clustered vessels. In some cases, vessels are surrounded by collagen deposits (blue stain, B, F, G). A: Lesion 1, cerebellum. B: Lesion 1. Masson trichrome stain. C: Lesion 2, motor cortex. D: Lesion 2. Masson trichrome stain. E: Lesion 3, adjacent to fourth ventricle. F: Lesion 3. Masson trichrome stain. G: Lesion 4, cerebellum. Masson trichrome stain. H: Lesion 5, third ventricle. H&E stain. Original magnifications: ×40 (B, D, H); ×200 (F, G).
Figure 2
Figure 2
Vessels within lesions are lined by a single layer of endothelium and lack a muscular wall. A: Lesion 1 stained with anti-Von Willibrand’s factor antibody. B: H&E stain of adjacent section. C: Lesion 1 stained with anti-α-SMA. D: H&E stain of adjacent section. E: Normal artery and vein from same brain stained with anti-α-SMA. F: H&E stain of normal artery and vein. Ar, artery; Ve, vein. Original magnifications, ×200.
Figure 3
Figure 3
Some vessels within lesions fail to express laminin. A: Lesion 1 stained with anti-laminin. B: H&E stain of adjacent section. C: Normal capillaries close to lesion 1 stained with anti-laminin. D: Lesion 2 stained with anti-laminin. Original magnifications: ×200 (A–C); ×100 (D).
Figure 4
Figure 4
Thrombosis, calcification, and hemosiderin deposits are visible within lesions. In these H&E-stained sections, thrombi (yellow arrows) appear pink, whereas calcifications (black arrows) stain dark blue. Hemosiderin is visible as brownish pigment within the cytoplasm of macrophages (C). A: Lesion 1. B: Lesion 3. C: Lesion 1. Original magnifications: ×40 (A); ×100 (B); ×400 (C).
Figure 5
Figure 5
Microhemorrhage and irregular blood vessels in brains of Ccm1+/− mice may be an early stage in growth of a cavernous malformation. A: Ccm1+/−Trp53−/−, H&E. B: B6;129-Ccm1+/− F1, H&E. Original magnifications: ×200 (A); ×∼300 (B).
Figure 6
Figure 6
Analysis of a tetra-nucleotide microsatellite linked to Ccm1 shows no evidence of LOH in a mouse lesion. No loss of the wild-type C57BL/6J allele is observed in several tissue samples isolated from lesion 1 by laser capture microdissection. Lane 1, normal cerebellar parenchyma from the opposite hemisphere; lane 2, cerebellar parenchyma flanking the lesion; lane 3, vascular endothelium from the lesion; lane 4, interstitial tissue from the lesion; lane 5, C57BL/6J DNA; lane 6, 129×1/SvJ DNA; lane 7, Ccm1+/− DNA; lane 8, water control.

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