Lack of CCM1 Induces Hypersprouting and Impairs Response to Flow.

Human molecular genetics

PubMedID: 24990152

Mleynek TM, Chan A, Redd M, Gibson CC, Davis C, Shi DS, Chen T, Carter KL, Ling J, Blanco R, Gerhardt H, Whitehead K, Li DY. Lack of CCM1 Induces Hypersprouting and Impairs Response to Flow. Hum Mol Genet. 2014;.
Cerebral Cavernous Malformation (CCM) is a disease of vascular malformations known to be caused by mutations in one of three genes: CCM1, CCM2, or CCM3. Despite several studies, the mechanism of CCM lesion onset remains unclear. Using a Ccm1 knockout mouse model, we studied the morphogenesis of early lesion formation in the retina in order to provide insight into potential mechanisms. We demonstrate that lesions develop in a stereotypic location and pattern, preceded by endothelial hypersprouting as confirmed in a zebrafish model of disease. The vascular defects seen with loss of Ccm1 suggest a defect in endothelial flow response. Taken together, these results suggest new mechanisms of early CCM disease pathogenesis and provide a framework for further study.