Bleeding owing to cerebral cavernous malformations (CCM) is involved in 10 percent of young patients who show cerebral hemorrhage. These cerebral vascular malformations can result from either sporadic or familial autosomal dominant (FCCM) conditions. Recurrent bleeding is the major complication in patients affected by FCCM, which is characterized by the presence of multiple CCM lesions. FCCM is caused by loss-of-function mutations in any of the three CCM genes identified so far. High expression levels of the CCM genes in the neuroepithelium indicate that CCM lesions may be caused by a loss of function of CCM genes in neural cells rather than in vascular cells. In vitro data suggest that CCM proteins are members of a large signaling complex involved in cell-cell junction homeostasis and cytoskeleton remodeling; however, their in vivo function, particularly during cerebral angiogenesis, is totally unknown and the mechanisms leading to the formation of CCM lesions are obscure.
Here, we used constitutive and tissue-specific inactivation of CCM2 to investigate its role in vascular development in the mouse. Constitutive deletion of CCM2 leads to an early embryonic death. Deletion of CCM2 from neuroglial precursor cells by using nestin-Cre transgenic mice results in mice with a normal phenotype, whereas deletion of CCM2 from endothelial cells by using Tie2-Cre transgenic mice severely hampers angiogenesis, leading to morphogenic defects in the major arterial and venous blood vessels and in the heart, and results in embryonic lethality at mid-gestation.
This study provides the first definitive demonstration that, despite the strong neuroepithelial expression of CCM2, it is the endothelial expression of CCM2 that is crucial for proper angiogenesis. It also strongly suggests that the endothelial cell is the primary target in the cascade of events leading from CCM2 mutations to CCM cerebrovascular lesions. These findings have important implications for the understanding of the mechanisms surrounding CCM lesion development. They indicate that development of these vascular lesions, which are found almost exclusively within the brain, may require additional events to take place within the cerebral environment, which have yet to be identified.
