Recent insights into cerebral cavernous malformations: animal models of CCM and the human phenotype

Abstract

Cerebral cavernous malformations are common vascular lesions of the central nervous system that predispose to seizures, focal neurologic deficits and potentially fatal hemorrhagic stroke. Human genetic studies have identified three genes associated with the disease and biochemical studies of these proteins have identified interaction partners and possible signaling pathways. A variety of animal models of CCM have been described to help translate the cellular and biochemical insights into a better understanding of disease mechanism. In this minireview, we discuss the contributions of animal models to our growing understanding of the biology of cavernous malformations, including the elucidation of the cellular context of CCM protein actions and the in vivo confirmation of abnormal endothelial cell-cell interactions. Challenges and progress towards developing a faithful model of CCM biology are reviewed.

Fig. 1

Conservation of CCM proteins across species. Similarity scores were generated for the three CCM proteins in comparison with human protein sequences (KRIT1, accession number AAH98442; CCM2, accession number AAH16832; PDCD10, accession number NP_665859). Protein sequences or predicted protein sequences for a variety of vertebrate and nonvertebrate species were included if similarity was detected by BLASTp algorithm across a full-length protein sequence. Blank fields represent species for which an orthologous gene has yet to be identified in available databases. All three proteins are well conserved across species, and are found in nonvertebrate species. Conservation is particularly strong for PDCD10, the smallest of the three proteins. Note that Pdcd10 has been duplicated in the zebrafish genome; the two proteins are denoted (a) and (b). C. elegans, Caenorhabditis elegans.

Fig. 2

Histology of CCM. Masson trichrome stain of surgically excised cavernous malformation. (A) Low-magnification view of CCM and surrounding brain. Hyalinized caverns of varying size are observed, surrounded by a rim of collagen deposits (blue). The adjacent brain shows evidence of gliosis (red). (B) Higher magnification view of boxed area. The caverns are lined by a single layer of endothelium (arrowheads) without smooth muscle support. Rather than smooth muscle cells or pericytes, a hyalinized rim of collagen surrounds the caverns (asterisks). Brown hemosiderin deposits are observed in the surrounding gliotic brain tissue (arrows).

Fig. 3

Narrowed arteries associated with circulation failure in mice lacking Ccm2. The connections of the heart to the aorta, and the associated cranial portions of the dorsal aorta are narrowed in mice lacking Ccm2. The paired dorsal aortae in a wild-type embryo at E9.0 are shown in (A) (arrows), stained for the endothelial marker CD31. Although endothelial cells are present in the correct location in a Ccm2 gene trap mutant littermate (arrows in B), little to no lumen is formed to support circulation.