martes, 20 de julio de 2010

Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling


Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling
Joycelyn Wüstehubea,b,1, Arne Bartola,b,1, Sven S. Lieblera,b, René Brütscha, Yuan Zhuc, Ute Felbord, Ulrich Surec, Hellmut G. Augustina,b, and Andreas Fischera,b,2

+ Author Affiliations

aVascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany;
bVascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), D-69120 Heidelberg, Germany;
cDepartment of Neurosurgery, University Hospital Essen, D-45122 Essen, Germany; and
dInstitute of Human Genetics, University Hospital Greifswald, D-17475 Greifswald, Germany
Edited by Napoleone Ferrara, Genentech, Inc., South San Francisco, CA, and approved June 7, 2010 (received for review January 7, 2010)

↵1J.W. and A.B. contributed equally to this work.

Abstract
Cerebral cavernous malformations (CCM) are frequent vascular abnormalities caused by mutations in one of the CCM genes. CCM1 (also known as KRIT1) stabilizes endothelial junctions and is essential for vascular morphogenesis in mouse embryos. However, cellular functions of CCM1 during the early steps of the CCM pathogenesis remain unknown. We show here that CCM1 represents an antiangiogenic protein to keep the human endothelium quiescent. CCM1 inhibits endothelial proliferation, apoptosis, migration, lumen formation, and sprouting angiogenesis in primary human endothelial cells. CCM1 strongly induces DLL4-NOTCH signaling, which promotes AKT phosphorylation but reduces phosphorylation of the mitogen-activated protein kinase ERK. Consistently, blocking of NOTCH activity alleviates CCM1 effects. ERK phosphorylation is increased in human CCM lesions. Transplantation of CCM1-silenced human endothelial cells into SCID mice recapitulates hallmarks of the CCM pathology and serves as a unique CCM model system. In this setting, the multikinase inhibitor Sorafenib can ameliorate loss of CCM1-induced excessive microvascular growth, reducing the microvessel density to levels of normal wild-type endothelial cells. Collectively, our data suggest that the origin of CCM lesions is caused by perturbed Notch signaling-induced excessive capillary sprouting, which can be therapeutically targeted.
http://www.pnas.org/content/107/28/12640

open here to see the original research:
http://www.pnas.org/content/107/28/12640.full.pdf+html

To whom correspondence should be addressed. E-mail:
andreas.fischer@medma.uni-heidelberg.de. Author contributions: J.W., A.B., S.S.L., R.B., Y.Z., H.G.A., and A.F. designed research; J.W., A.B., S.S.L., R.B., Y.Z., and A.F. performed research; U.F., U.S., and H.G.A. contributed new reagents/analytic tools; J.W., A.B., S.S.L., R.B., Y.Z., and A.F. analyzed data; and J.W., H.G.A., and A.F. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE18014).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1000132107/-/DCSupplemental.

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