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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2014     Display Documents

ID: 682148.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2014
G13 controls angiogenesis through regulation of VEGFR-2 expression
Authors:Sivaraj, K. K.; Takefuji, M.; Schmidt, I.; Adams, R. H.; Offermanns, S.; Wettschureck, N.
Date of Publication (YYYY-MM-DD):2013-05-28
Journal Abbrev.:Dev Cell
Issue / Number:4
Start Page:427
End Page:434
Audience:Not Specified
Abstract / Description:At sites of angiogenesis, the expression of the key angiogenesis regulator vascular endothelial growth factor (VEGF) and its main receptor, VEGF receptor 2 (VEGFR-2), are strongly upregulated. Whereas the processes controlling VEGF expression are well described, the mechanisms underlying VEGFR-2 upregulation have remained unclear. We found that endothelial VEGFR-2 expression is strongly reduced in the absence of the G protein G13, resulting in an impaired responsiveness to VEGF-A, a phenotype that can be rescued by normalization of VEGFR-2 levels. G13-mediated VEGFR-2 expression involved activation of the small GTPase RhoA and transcription factor NF-kappaB, the latter acting via a specific binding site at position -84 of the VEGFR-2 promoter. Mice with endothelial cell-specific loss of G13 showed reduced VEGFR-2 expression at sites of angiogenesis and attenuated VEGF effects, resulting in impaired retinal angiogenesis and tumor vascularization. Taken together, we identified G-protein-mediated signaling via G13 as a critical regulator of VEGFR-2 expression during angiogenesis.
Free Keywords:Alleles; Animals; Cell Line, Tumor; Endothelium/*blood supply/metabolism; GTP-Binding Protein alpha Subunits, G12-G13/genetics/*metabolism; *Gene Expression Regulation, Neoplastic; Human Umbilical Vein Endothelial Cells; Humans; Lung/metabolism/pathology; Mice; Mice, Inbred C57BL; NF-kappa B/genetics/metabolism; Neovascularization, Pathologic/genetics/*metabolism; Promoter Regions, Genetic; Proprotein Convertases/genetics/metabolism; RNA, Small Interfering/genetics/metabolism; Retina/drug effects/metabolism/pathology; Retinal Vessels/metabolism/pathology; Serine Endopeptidases/genetics/metabolism; Tamoxifen/pharmacology; Vascular Endothelial Growth Factor Receptor-2/genetics/*metabolism; rho GTP-Binding Proteins/genetics/metabolism
External Publication Status:published
Document Type:Article
Communicated by:Svea Hümmer
Affiliations:MPI für physiologische und klinische Forschung
Identifiers:ISSN:1878-1551 (Electronic) 1534-5807 (Linking) %R 10.1016/j.devcel.2013.04.008
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