Lack of CCM1 induces hypersprouting and impairs response to flow
Authors
- T.M. Mleynek
- A.C. Chan
- M. Redd
- C.C. Gibson
- C.T. Davis
- D.S. Shi
- T. Chen
- K.L. Carter
- J. Ling
- R. Blanco
- H. Gerhardt
- K. Whitehead
- D.Y. Li
Journal
- Human Molecular Genetics
Citation
- Hum Mol Genet 23 (23): 6223-6234
Abstract
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.