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

Enrico Giraudo, Luca Primo, Enrica Audero, Hans Peter Gerber, Pieter Koolwijk, Shay Soker, Michael Klagsbrun, Napoleone Ferrara, Federico Bussolino

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)22128-22135
Number of pages8
JournalJournal of Biological Chemistry
Volume273
Issue number34
DOIs
Publication statusPublished - Aug 21 1998

ASJC Scopus subject areas

  • Biochemistry

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