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Tumor necrosis factor-α regulates expression of vascular endothelial growth factor receptor-2 and of its co-receptor neuropilin-1 in human vascular endothelial cells

Author: Giraudo, E. · Primo, L. · Audero, E. · Gerber, H.-P. · Koolwijk, P. · Soker, S. · Klagsbrun, M. · Ferrara, N. · Bussolino, F.
Institution: TNO Preventie en Gezondheid
Source:Journal of Biological Chemistry, 34, 273, 22128-22135
Identifier: 234584
doi: doi:10.1074/jbc.273.34.22128
Keywords: 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


Tumor necrosis factor-α (TNF-α) modulates gene expression in endothelial cells and is angiogenic in vivo. TNF-α 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-α 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-α 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-α 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-α is angiogenic and may provide insight into the mechanism of neovascularization as occurs in TNF- α-mediated pathological settings.