Abstract
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-κB, 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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alleles
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Animals
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Cell Line, Tumor
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Endothelium / blood supply*
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Endothelium / metabolism
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GTP-Binding Protein alpha Subunits, G12-G13 / genetics
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GTP-Binding Protein alpha Subunits, G12-G13 / metabolism*
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Gene Expression Regulation, Neoplastic*
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Human Umbilical Vein Endothelial Cells
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Humans
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Lung / metabolism
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Lung / pathology
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Mice
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Mice, Inbred C57BL
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism*
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Promoter Regions, Genetic
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Proprotein Convertases / genetics
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Proprotein Convertases / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Retina / drug effects
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Retina / metabolism
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Retina / pathology
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Retinal Vessels / metabolism
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Retinal Vessels / pathology
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Serine Endopeptidases / genetics
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Serine Endopeptidases / metabolism
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Tamoxifen / pharmacology
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / metabolism*
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rho GTP-Binding Proteins / genetics
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rho GTP-Binding Proteins / metabolism
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rhoA GTP-Binding Protein
Substances
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NF-kappa B
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RNA, Small Interfering
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Tamoxifen
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Vascular Endothelial Growth Factor Receptor-2
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Proprotein Convertases
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Serine Endopeptidases
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membrane-bound transcription factor peptidase, site 1
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GTP-Binding Protein alpha Subunits, G12-G13
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RhoA protein, mouse
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rho GTP-Binding Proteins
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rhoA GTP-Binding Protein