title: Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling.
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.
authors.affiliation: Vascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany.
authors.forename: Joycelyn
authors.initials: J
authors.lastname: Wüstehube
authors.forename: Arne
authors.initials: A
authors.lastname: Bartol
authors.forename: Sven S
authors.initials: SS
authors.lastname: Liebler
authors.forename: René
authors.initials: R
authors.lastname: Brütsch
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Ute
authors.initials: U
authors.lastname: Felbor
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sure
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.forename: Andreas
authors.initials: A
authors.lastname: Fischer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D016513:Mice, SCID; D055806:Microvessels; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D009154:Mutation; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases