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

Kevin J. Whitehead, Aubrey C. Chan, Sutip Navankasattusas, Wonshill Koh, Nyall R. London, Jing Ling, Anne H. Mayo, Stavros G. Drakos, Douglas A. Marchuk, George E. Davis, Dean Y. Li

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)177-184
Number of pages8
JournalNature medicine
Volume15
Issue number2
DOIs
StatePublished - Feb 1 2009
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Whitehead, K. J., Chan, A. C., Navankasattusas, S., Koh, W., London, N. R., Ling, J., Mayo, A. H., Drakos, S. G., Marchuk, D. A., Davis, G. E., & Li, D. Y. (2009). The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nature medicine, 15(2), 177-184. https://doi.org/10.1038/nm.1911