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

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.

Pubmed ID: 19151728

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

Journal

Nature medicine

Publication Data

February 6, 2009

Associated Grants

  • Agency: NHLBI NIH HHS, Id: K02 HL069774
  • Agency: NHLBI NIH HHS, Id: K02 HL069774-05
  • Agency: NHLBI NIH HHS, Id: K08 HL079095
  • Agency: NHLBI NIH HHS, Id: K08 HL079095-03
  • Agency: NHLBI NIH HHS, Id: R01 HL065648
  • Agency: NHLBI NIH HHS, Id: R01 HL068873
  • Agency: NHLBI NIH HHS, Id: R01 HL068873-05
  • Agency: NHLBI NIH HHS, Id: R01 HL068873-06
  • Agency: NHLBI NIH HHS, Id: R01 HL077671
  • Agency: NHLBI NIH HHS, Id: R01 HL077671-04
  • Agency: NHLBI NIH HHS, Id: R01 HL084516
  • Agency: NHLBI NIH HHS, Id: R01 HL084516-02
  • Agency: NIGMS NIH HHS, Id: T32-GM007464

Mesh Terms

  • Animals
  • Blood Vessels
  • Carrier Proteins
  • Heterozygote
  • Humans
  • Mice
  • Signal Transduction
  • rho GTP-Binding Proteins