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

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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Evdokia Dimitriadis, Daniel L. Rolnik, … Ellen Menkhorst

Change history

  • 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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Correspondence to Kevin J Whitehead or Dean Y Li.

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The University of Utah has filed patents on the basis of the results reported in this paper.

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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