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          Institute: MPI für molekulare Biomedizin     Collection: Yearbook 2013     Display Documents



  history
ID: 648319.0, MPI für molekulare Biomedizin / Yearbook 2013
Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling
Authors:Benedito, R.; Rocha, S. F.; Woeste, M.; Zamykal, M.; Radtke, F.; Casanovas, O.; Duarte, A.; Pytowski, B.; Adams, R. H.
Date of Publication (YYYY-MM-DD):2012-04-05
Title of Journal:Nature
Volume:484
Issue / Number:7392
Start Page:110
End Page:114
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Developing tissues and growing tumours produce vascular endothelial growth factors (VEGFs), leading to the activation of the corresponding receptors in endothelial cells. The resultant angiogenic expansion of the local vasculature can promote physiological and pathological growth processes. Previous work has uncovered that the VEGF and Notch pathways are tightly linked. Signalling triggered by VEGF-A (also known as VEGF) has been shown to induce expression of the Notch ligand DLL4 in angiogenic vessels and, most prominently, in the tip of endothelial sprouts. DLL4 activates Notch in adjacent cells, which suppresses the expression of VEGF receptors and thereby restrains endothelial sprouting and proliferation. Here we show, by using inducible loss-of-function genetics in combination with inhibitors in vivo, that DLL4 protein expression in retinal tip cells is only weakly modulated by VEGFR2 signalling. Surprisingly, Notch inhibition also had no significant impact on VEGFR2 expression and induced deregulated endothelial sprouting and proliferation even in the absence of VEGFR2, which is the most important VEGF-A receptor and is considered to be indispensable for these processes. By contrast, VEGFR3, the main receptor for VEGF-C, was strongly modulated by Notch. VEGFR3 kinase-activity inhibitors but not ligand-blocking antibodies suppressed the sprouting of endothelial cells that had low Notch signalling activity. Our results establish that VEGFR2 and VEGFR3 are regulated in a highly differential manner by Notch. We propose that successful anti-angiogenic targeting of these receptors and their ligands will strongly depend on the status of endothelial Notch signalling.
Free Keywords:Animals; Cells, Cultured; Endothelial Cells/cytology/drug effects/metabolism; Female; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Intracellular Signaling Peptides and Proteins/deficiency/genetics/metabolism; Male; Membrane Proteins/deficiency/genetics/metabolism; Mice; Models, Biological; Neovascularization, Physiologic/drug effects/*physiology; Protein Kinase Inhibitors/pharmacology; Receptors, Notch/antagonists & inhibitors/*metabolism; *Signal Transduction/drug effects; Transcription, Genetic; *Up-Regulation; Vascular Endothelial Growth Factor A/*metabolism; Vascular Endothelial Growth Factor Receptor-2/deficiency/genetics/*metabolism; Vascular Endothelial Growth Factor Receptor-3/biosynthesis/genetics/*metabolism
External Publication Status:published
Document Type:Article
Communicated by:keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:%G eng
Identifiers:ISSN:1476-4687 (Electronic) 0028-0836 (Linking) %R 10.1... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/22426001 [ID No:2]
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