The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases.

Published

Journal Article

Cerebral cavernous malformation (CCM) is a common vascular dysplasia that affects both systemic and central nervous system blood vessels. Loss of function mutations in the CCM2 gene cause CCM. Here we show that targeted disruption of Ccm2 in mice results in failed lumen formation and early embryonic death through an endothelial cell autonomous mechanism. We show that CCM2 regulates endothelial cytoskeletal architecture, cell-to-cell interactions and lumen formation. Heterozygosity at Ccm2, a genotype equivalent to that in human CCM, results in impaired endothelial barrier function. On the basis of our biochemical studies indicating that loss of CCM2 results in activation of RHOA GTPase, we rescued the cellular phenotype and barrier function in heterozygous mice with simvastatin, a drug known to inhibit Rho GTPases. These data offer the prospect for pharmacological treatment of a human vascular dysplasia with a widely available and safe drug.

Full Text

Duke Authors

Cited Authors

  • Whitehead, KJ; Chan, AC; Navankasattusas, S; Koh, W; London, NR; Ling, J; Mayo, AH; Drakos, SG; Jones, CA; Zhu, W; Marchuk, DA; Davis, GE; Li, DY

Published Date

  • February 2009

Published In

Volume / Issue

  • 15 / 2

Start / End Page

  • 177 - 184

PubMed ID

  • 19151728

Pubmed Central ID

  • 19151728

Electronic International Standard Serial Number (EISSN)

  • 1546-170X

Digital Object Identifier (DOI)

  • 10.1038/nm.1911

Language

  • eng

Conference Location

  • United States