Title
Tumor necrosis factor-alpha regulates expression of vascular endothelial growth factor receptor-2 and of its co-receptor neuropilin-1 in human vascular endothelial cells
Author
TNO Preventie en Gezondheid
Giraudo, E.
Primo, L.
Audero, E.
Gerber, H.P.
Koolwijk, P.
Soker, S.
Klagsbrun, M.
Ferrara, N.
Bussolino, F.
Publication year
1998
Abstract
Tumor necrosis factor-alpha (TNF-alpha) modulates gene expression in endothelial cells and is angiogenic in vivo. TNF-alpha does not activate in vitro migration and proliferation of endothelium, and its angiogenic activity is elicited by synthesis of direct angiogenic inducers or of proteases. Here, we show that TNF-alpha up-regulates in a dose- and time-dependent manner the expression and the function of vascular endothelial growth factor receptor-2 (VEGFR-2) as well as the expression of its coreceptor neuropilin-1 in human endothelium. As inferred by nuclear run-on assay and transient expression of VEGFR-2 promoter-based reporter gene construct, the cytokine increased the transcription of the VEGFR-2 gene. Mithramycin, an inhibitor of binding of nuclear transcription factor Sp1 to the promoter consensus sequence, blocked activation of VEGFR-2, suggesting that the up-regulation of the receptor required Sp1 binding sites. TNF-alpha increased the cellular amounts of VEGFR-2 protein and tripled the high affinity 125I-VEGF-A165 capacity without affecting the K(d) of ligand-receptor interaction. As a consequence, TNF-alpha enhanced the migration and the wound healing triggered by VEGF-A165. Since VEGFR-2 mediates angiogenic signals in endothelium, our data indicate that its up-regulation is another mechanism by which TNF-alpha is angiogenic and may provide insight into the mechanism of neovascularization as occurs in TNF- alpha-mediated pathological settings.
Subject
Antigens, Surface
Cells, Cultured
Endothelium, Vascular
Gene Expression Regulation
Humans
Kinetics
Membrane Glycoproteins
Nerve Tissue Proteins
Neuropilin-1
Receptor Protein-Tyrosine Kinases
Receptors, Cell Surface
Receptors, Growth Factor
Receptors, Vascular Endothelial Growth Factor
RNA, Messenger
Tumor Necrosis Factor-alpha
Up-Regulation
Wound Healing
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DOI
https://doi.org/10.1074/jbc.273.34.22128
TNO identifier
234584
ISSN
0021-9258
Source
Journal of Biological Chemistry, 273 (273), 22128-22135
Document type
article