Article abstract


Nature Medicine 15, 177 - 184 (2009)
Published online: 18 January 2009 | Corrected online: 6 April 2009 | doi:10.1038/nm.1911



There is a Corrigendum (April 2009) associated with this Article.

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

Kevin J Whitehead1,2, Aubrey C Chan2, Sutip Navankasattusas2, Wonshill Koh3, Nyall R London2, Jing Ling2, Anne H Mayo3, Stavros G Drakos2, Christopher A Jones2, Weiquan Zhu2, Douglas A Marchuk4, George E Davis3 & Dean Y Li1,2


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.

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  1. Division of Cardiology, Department of Medicine, 30 North 1900 East, Room 4A100, University of Utah, Salt Lake City, Utah 84132, USA.
  2. Molecular Medicine Program, 15 North 2030 East, Room 4140, University of Utah, Salt Lake City, Utah 84112, USA.
  3. The Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, MA415 Medical Sciences Building, One Hospital Drive, Columbia, Missouri 65212, USA.
  4. Department of Molecular Genetics and Microbiology, Box 3175, Duke University Medical Center, Durham, North Carolina 27710, USA.

Correspondence to: Kevin J Whitehead1,2 e-mail: kevin.whitehead@hsc.utah.edu

Correspondence to: Dean Y Li1,2 e-mail: dean.li@hmbg.utah.edu

* In the version of this article initially published, Christopher A. Jones and Weiquan Zhu were not included in the list of authors. The error has been corrected in the HTML and PDF versions of the article.

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