title: Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development.
abstract: Cerebral cavernous malformations (CCMs) are human vascular malformations caused by mutations in three genes of unknown function: CCM1, CCM2, and CCM3. CCM3, also known as PDCD10 (programmed cell death 10), was initially identified as a messenger RNA whose abundance was induced by apoptotic stimuli in vitro. However, the in vivo function of CCM3 has not been determined. Here, we describe mice with a deletion of the CCM3 gene either ubiquitously or specifically in the vascular endothelium, smooth muscle cells, or neurons. Mice with global or endothelial cell-specific deletion of CCM3 exhibited defects in embryonic angiogenesis and died at an early embryonic stage. CCM3 deletion reduced vascular endothelial growth factor receptor 2 (VEGFR2) signaling in embryos and endothelial cells. In response to VEGF stimulation, CCM3 was recruited to and stabilized VEGFR2, and the carboxyl-terminal domain of CCM3 was required for the stabilization of VEGFR2. Indeed, the CCM3 mutants found in human patients lacking the carboxyl-terminal domain were labile and were unable to stabilize and activate VEGFR2. These results demonstrate that CCM3 promotes VEGFR2 signaling during vascular development.
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, 10 Amistad Street, New Haven, CT 06520, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: He
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.forename: Luyang
authors.initials: L
authors.lastname: Yu
authors.forename: Murat
authors.initials: M
authors.lastname: Gunel
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Wang
authors.initials: W
authors.lastname: Min
mesh_terms: D000818:Animals; D002319:Cardiovascular System / Q000196:embryology*; D042783:Endothelial Cells / Q000502:physiology; D019084:Fluorescent Antibody Technique, Indirect; D017353:Gene Deletion; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D040301:Vascular Endothelial Growth Factor Receptor-2