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Cerebral cavernous malformations (CCMs) are vascular lesions of the central nervous system appearing as multicavernous, blood-filled capillaries, leading to headache, seizure and hemorrhagic stroke. CCM occurs either sporadically or as an autosomal dominant disorder caused by germline mutation of one of the three genes:  CCM1 / KRIT1 ,  CCM2 / MGC4607  and  CCM3 / PDCD10 . Surgically resected human CCM lesions have provided molecular and immunohistochemical evidence for a two-hit (germline plus somatic) mutation mechanism. In contrast to the equivalent human genotype, mice heterozygous for a  Ccm1 - or  Ccm2 -null allele do not develop CCM lesions. Based on the two-hit hypothesis, we attempted to improve the penetrance of the model by crossing  Ccm1  and  Ccm2  heterozygotes into a mismatch repair-deficient  Msh2  −/−  background.  Ccm1  +/−  Msh2  −/−  mice exhibit CCM lesions with high penetrance as shown by magnetic resonance imaging and histology. Significantly, the CCM lesions range in size from early-stage, isolated caverns to large, multicavernous lesions. A subset of endothelial cells within the CCM lesions revealed somatic loss of CCM protein staining, supporting the two-hit mutation mechanism. The late-stage CCM lesions displayed many of the characteristics of human CCM lesions, including hemosiderin deposits, immune cell infiltration, increased endothelial cell proliferation and increased Rho-kinase activity. Some of these characteristics were also seen, but to a lesser extent, in early-stage lesions. Tight junctions were maintained between CCM lesion endothelial cells, but gaps were evident between endothelial cells and basement membrane was defective. In contrast, the  Ccm2  +/−  Msh2  −/−  mice lacked cerebrovascular lesions. The CCM1 mouse model provides an  in vivo  tool to investigate CCM pathogenesis and new therapies.

A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease