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

Publication ,  Journal Article
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 in: Nat Med
February 2009

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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Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

February 2009

Volume

15

Issue

2

Start / End Page

177 / 184

Location

United States

Related Subject Headings

  • rho GTP-Binding Proteins
  • Signal Transduction
  • Mice
  • Immunology
  • Humans
  • Heterozygote
  • Carrier Proteins
  • Blood Vessels
  • Animals
  • 42 Health sciences
 

Citation

APA
Chicago
ICMJE
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Whitehead, K. J., Chan, A. C., Navankasattusas, S., Koh, W., London, N. R., Ling, J., … Li, D. Y. (2009). The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat Med, 15(2), 177–184. https://doi.org/10.1038/nm.1911
Whitehead, Kevin J., Aubrey C. Chan, Sutip Navankasattusas, Wonshill Koh, Nyall R. London, Jing Ling, Anne H. Mayo, et al. “The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases.Nat Med 15, no. 2 (February 2009): 177–84. https://doi.org/10.1038/nm.1911.
Whitehead KJ, Chan AC, Navankasattusas S, Koh W, London NR, Ling J, et al. The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat Med. 2009 Feb;15(2):177–84.
Whitehead, Kevin J., et al. “The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases.Nat Med, vol. 15, no. 2, Feb. 2009, pp. 177–84. Pubmed, doi:10.1038/nm.1911.
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. The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat Med. 2009 Feb;15(2):177–184.

Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

February 2009

Volume

15

Issue

2

Start / End Page

177 / 184

Location

United States

Related Subject Headings

  • rho GTP-Binding Proteins
  • Signal Transduction
  • Mice
  • Immunology
  • Humans
  • Heterozygote
  • Carrier Proteins
  • Blood Vessels
  • Animals
  • 42 Health sciences