G13 controls angiogenesis through regulation of VEGFR-2 expression

Dev Cell. 2013 May 28;25(4):427-34. doi: 10.1016/j.devcel.2013.04.008. Epub 2013 May 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cell Line, Tumor
  • Endothelium / blood supply*
  • Endothelium / metabolism
  • GTP-Binding Protein alpha Subunits, G12-G13 / genetics
  • GTP-Binding Protein alpha Subunits, G12-G13 / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism*
  • Promoter Regions, Genetic
  • Proprotein Convertases / genetics
  • Proprotein Convertases / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Retina / drug effects
  • Retina / metabolism
  • Retina / pathology
  • Retinal Vessels / metabolism
  • Retinal Vessels / pathology
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism
  • Tamoxifen / pharmacology
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism
  • rhoA GTP-Binding Protein

Substances

  • NF-kappa B
  • RNA, Small Interfering
  • Tamoxifen
  • Vascular Endothelial Growth Factor Receptor-2
  • Proprotein Convertases
  • Serine Endopeptidases
  • membrane-bound transcription factor peptidase, site 1
  • GTP-Binding Protein alpha Subunits, G12-G13
  • RhoA protein, mouse
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein