title: G13 controls angiogenesis through regulation of VEGFR-2 expression.
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.
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Kishor Kumar
authors.initials: KK
authors.lastname: Sivaraj
authors.forename: Mikito
authors.initials: M
authors.lastname: Takefuji
authors.forename: Inga
authors.initials: I
authors.lastname: Schmidt
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Nina
authors.initials: N
authors.lastname: Wettschureck
mesh_terms: D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor; D004727:Endothelium / Q000098:blood supply* / Q000378:metabolism; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D016328:NF-kappa B; D034741:RNA, Small Interfering; D013629:Tamoxifen; D040301:Vascular Endothelial Growth Factor Receptor-2; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1; D044365:GTP-Binding Protein alpha Subunits, G12-G13; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein