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Lack of CCM1 induces hypersprouting and impairs response to flow

2014; Oxford University Press; Volume: 23; Issue: 23 Linguagem: Inglês

10.1093/hmg/ddu342

1460-2083

Tara Mleynek, Aubrey C. Chan, Michael Redd, Christopher C. Gibson, Chadwick T. Davis, Dallas Shi, Tiehua Chen, Kandis L. Carter, Ling Jing, Raquel Blanco, Holger Gerhardt, Kevin J. Whitehead, Dean Y. Li,

Retinal and Macular Surgery

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.