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

Nature Medicine volume 15, pages 177–184 (2009)Cite this article

A Corrigendum to this article was published on 01 April 2009

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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.

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Figure 1: Ccm2 is required for blood circulation.
Figure 2: Vascular defects in mutant mice are endothelial cell autonomous.
Figure 3: CCM2 is required for endothelial tube morphogenesis.
Figure 4: CCM2 deficiency alters the endothelial cytoskeletal architecture and cell-cell interactions via activation of the small GTPase RHOA.
Figure 5: Heterozygous Ccm2+/tr mice have permeability defects that can be rescued by treatment with simvastatin.

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  • 06 April 2009

    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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Acknowledgements

We thank C. Colvin, C. Jones, W. Zhu and A. Frias for technical assistance; M. Sanguinetti, S. Odelberg and I. Benjamin for critical comments; M. Kahn, K. Thomas, M. Ginsberg and R. Stockton for helpful scientific discussions; and A. Hall (Memorial Sloan-Kettering Cancer Center) for GTPase complementary DNA constructs. This work was funded by the US National Institutes of Health (K.J.W., D.A.M., G.E.D. and D.Y.L.), including training grant T32-GM007464 (A.C.C.) and a Ruth L. Kirschstein National Research Service award (N.R.L.), the American Heart Association (K.J.W. and D.Y.L.), the H.A. and Edna Benning Foundation, the Juvenile Diabetes Research Foundation, the Burroughs Wellcome Fund and the Flight Attendants Medical Research Institute (D.Y.L.).

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Authors and Affiliations

  1. Division of Cardiology, Department of Medicine, 30 North 1900 East, Room 4A100, University of Utah, Salt Lake City, Utah 84132, USA.,

    Kevin J Whitehead & Dean Y Li

  2. Molecular Medicine Program, 15 North 2030 East, Room 4140, University of Utah, Salt Lake City, 84112, Utah, USA

    Kevin J Whitehead, Aubrey C Chan, Sutip Navankasattusas, Nyall R London, Jing Ling, Stavros G Drakos, Christopher A Jones, Weiquan Zhu & Dean Y Li

  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.,

    Wonshill Koh, Anne H Mayo & George E Davis

  4. Department of Molecular Genetics and Microbiology, Box 3175, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Douglas A Marchuk

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Correspondence to Kevin J Whitehead or Dean Y Li.

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Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1 and 2, Supplementary Table 1 and Supplementary Methods (PDF 746 kb)

Supplementary Movies 1

Fetal ultrasound of Ccm2+/+ embryo at E8.8. Circulating blood is observed (moving pixels) in the dorsal aorta and the yolk sac vessels of the embryo. (MOV 547 kb)

Supplementary Movies 2

Fetal ultrasound of Ccm2tr/tr embryo at E8.8. No circulating blood is observed, despite normal frequency of cardiac contractions. (MOV 486 kb)

Supplementary Movies 3

Time-lapse photography of luciferase control siRNA treated HUVECs. Observation over 24 h shows the formation of intracellular vacuoles that coalesce into multicellular networks with lumens. (MOV 4239 kb)

Supplementary Movies 4

Time-lapse photography of CCM2 siRNA–treated HUVECs. Observation over 24 h shows impairment of vacuole and lumen formation in cells depleted of CCM2. (MOV 4657 kb)

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Whitehead, K., Chan, A., Navankasattusas, S. et al. The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat Med 15, 177–184 (2009). https://doi.org/10.1038/nm.1911

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