Journal article
The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases
Nature medicine, Vol.15(2), pp.177-184
02/01/2009
DOI: 10.1038/nm.1911
PMCID: PMC2767168
PMID: 19151728
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.
Details
- Title: Subtitle
- The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases
- Creators
- Kevin J. Whitehead - DIVISION OF CARDIOVASCULAR MEDICINEAubrey C. Chan - University of UtahSutip Navankasattusas - University of UtahWonshill Koh - University of MissouriNyall R. London - University of UtahJing Ling - University of UtahAnne H. Mayo - University of MissouriStavros G. Drakos - DIVISION OF CARDIOVASCULAR MEDICINEChristopher A Jones - University of UtahWeiquan Zhu - University of UtahDouglas A. Marchuk - Duke UniversityGeorge E. Davis - University of MissouriDean Y. Li - MOLECULAR MEDICINE PROGRAM
- Resource Type
- Journal article
- Publication Details
- Nature medicine, Vol.15(2), pp.177-184
- Publisher
- Springer Nature
- DOI
- 10.1038/nm.1911
- PMID
- 19151728
- PMCID
- PMC2767168
- ISSN
- 1078-8956
- eISSN
- 1546-170X
- Number of pages
- 8
- Grant note
- T32GM007464 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) Edna Benning Foundation Juvenile Diabetes Research Foundation, the Burroughs; Juvenile Diabetes Research Foundation Ruth L. Kirschstein National Research Service award; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA American Heart Association R01HL077671 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) T32-GM007464 / US National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 02/01/2009
- Academic Unit
- Psychiatry; Internal Medicine
- Record Identifier
- 9984280874802771
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