학술논문
Contribution of vascular endothelial growth factor receptor-2 sialylation to the process of angiogenesis
Document Type
Report
Source
Oncogene. November 23, 2017, Vol. 36 Issue 47, p6531, 11 p.
Subject
Language
English
ISSN
0950-9232
Abstract
Author(s): P Chiodelli [sup.1] , S Rezzola [sup.1] , C Urbinati [sup.1] , F Federici Signori [sup.1] , E Monti [sup.2] , R Ronca [sup.1] , M Presta [sup.1] , [...]
Vascular endothelial growth factor receptor-2 (VEGFR2) is the main pro-angiogenic receptor expressed by endothelial cells (ECs). Using surface plasmon resonance, immunoprecipitation, enzymatic digestion, immunofluorescence and cross-linking experiments with specific sugar-binding lectins, we demonstrated that VEGFR2 bears both [alpha],1-fucose and [alpha](2,6)-linked sialic acid (NeuAc). However, only the latter is required for VEGF binding to VEGFR2 and consequent VEGF-dependent VEGFR2 activation and motogenic response in ECs. Notably, downregulation of [beta]-galactoside [alpha](2,6)-sialyltransferase expression by short hairpin RNA transduction inhibits VEGFR2 [alpha](2,6) sialylation that is paralleled by an increase of [beta]-galactoside [alpha](2,3)-sialyltransferase expression. This results in an ex-novo [alpha](2,3)-NeuAc sialylation of the receptor that functionally replaces the lacking [alpha](2,6)-NeuAc, thus allowing VEGF/VEGFR2 interaction. In keeping with the role of VEGFR2 sialylation in angiogenesis, the [alpha](2,6)-NeuAc-binding lectin Sambucus nigra (SNA) prevents VEGF-dependent VEGFR2 autophosphorylation and EC motility, proliferation and motogenesis. In addition, SNA exerts a VEGF-antagonist activity in tridimensional angiogenesis models in vitro and in the chick-embryo chorioallantoic membrane neovascularization assay and mouse matrigel plug assay in vivo. In conclusion, VEGFR2-associated NeuAc plays an important role in modulating VEGF/VEGFR2 interaction, EC pro-angiogenic activation and neovessel formation. VEGFR2 sialylation may represent a target for the treatment of angiogenesis-dependent diseases.
Vascular endothelial growth factor receptor-2 (VEGFR2) is the main pro-angiogenic receptor expressed by endothelial cells (ECs). Using surface plasmon resonance, immunoprecipitation, enzymatic digestion, immunofluorescence and cross-linking experiments with specific sugar-binding lectins, we demonstrated that VEGFR2 bears both [alpha],1-fucose and [alpha](2,6)-linked sialic acid (NeuAc). However, only the latter is required for VEGF binding to VEGFR2 and consequent VEGF-dependent VEGFR2 activation and motogenic response in ECs. Notably, downregulation of [beta]-galactoside [alpha](2,6)-sialyltransferase expression by short hairpin RNA transduction inhibits VEGFR2 [alpha](2,6) sialylation that is paralleled by an increase of [beta]-galactoside [alpha](2,3)-sialyltransferase expression. This results in an ex-novo [alpha](2,3)-NeuAc sialylation of the receptor that functionally replaces the lacking [alpha](2,6)-NeuAc, thus allowing VEGF/VEGFR2 interaction. In keeping with the role of VEGFR2 sialylation in angiogenesis, the [alpha](2,6)-NeuAc-binding lectin Sambucus nigra (SNA) prevents VEGF-dependent VEGFR2 autophosphorylation and EC motility, proliferation and motogenesis. In addition, SNA exerts a VEGF-antagonist activity in tridimensional angiogenesis models in vitro and in the chick-embryo chorioallantoic membrane neovascularization assay and mouse matrigel plug assay in vivo. In conclusion, VEGFR2-associated NeuAc plays an important role in modulating VEGF/VEGFR2 interaction, EC pro-angiogenic activation and neovessel formation. VEGFR2 sialylation may represent a target for the treatment of angiogenesis-dependent diseases.