Ccm1is required for arterial morphogenesis: implications for the etiology of human cavernous malformations

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Abstract
Hemorrhagic stroke is a significant cause of morbidity and mortality in children, and is frequently associated with intracranial vascular malformations. One prevalent form of these vascular malformations, cerebral cavernous malformation, is characterized by thin-walled vascular cavities that hemorrhage and has been linked to loss-of-function mutations in CCM1. The neural and epithelial expression of CCM1 in adulthood suggests that cavernous malformations may be the result of primary neural defects. In this study, we generated mice lacking Ccm1 and demonstrate that Ccm1 is ubiquitously expressed early in embryogenesis and is essential for vascular development. Homozygous mutant embryos die in mid-gestation and the first detectable defects are exclusively vascular in nature. The precursor vessels of the brain become dilated starting at E8.5, reminiscent of the intracranial vascular defects observed in the human disease. In addition, there is marked enlargement and increased endothelial proliferation of the caudal dorsal aorta, as well as variable narrowing of the branchial arch arteries and proximal dorsal aorta. These vascular defects are not secondary to primary neural defects, as neural morphology and marker expression are normal even subsequent to the onset of vascular pathology. The defects in the vascular structure of embryos lacking Ccm1 are associated with early downregulation of artery-specific markers, including the Efnb2- and Notch-related genes. Finally, consistent with the murine data, we found that there is an analogous reduction in Notch gene expression in arterioles from humans with mutations in CCM1. Our studies suggest that cavernous malformations result from primary vascular rather than neural defects.