Lack of CCM1 induces hypersprouting and impairs response to flow


  • 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


  • Human Molecular Genetics


  • Hum Mol Genet 23 (23): 6223-6234


  • 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.