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MBC in Press, published online ahead of print October 25, 2006
Mol. Biol. Cell 10.1091/mbc.E06-07-0596

A more recent version of this article appeared on January 1, 2007
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Submitted on July 12, 2006
Revised on September 29, 2006
Accepted on October 18, 2006

Synergistic Up-Regulation of Vascular Endothelial Growth Factor (VEGF) Expression in Macrophages by Adenosine A2A Receptor Agonists and Endotoxin Involves Transcriptional Regulation via the Hypoxia Response Element (HRE) in the VEGF Promoter

Madhuri Ramanathan, Grace Pinhal-Enfield, Irene Hao, and Samuel Joseph Leibovich

Department of Cell Biology and Molecular Medicine and The Cardiovascular Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey (UMDNJ), Newark, NJ 07103

Monitoring Editor: Richard Assoian

Macrophages are an important source of VEGF. Adenosine A2A receptor (A2AR) agonists with Toll-like receptor (TLR) 2, 4, 7, and 9 agonists synergistically induce macrophage VEGF expression. We show here using VEGF promoter-luciferase reporter constructs that the TLR4 agonist Escherichia coli LPS and the A2AR agonists NECA and CGS21680 synergistically augment VEGF transcription in macrophages, and that the HRE in the VEGF promoter is essential for this transcription. We examined whether LPS and/or NECA induce HIF-1{alpha} expression. HIF-1{alpha} mRNA levels were increased in LPS-treated macrophages in an NF-{kappa}B-dependent manner; NECA strongly increased these levels in an A2AR-dependent manner. LPS induced luciferase expression from a HIF-1{alpha} promoter-luciferase construct in an A2AR-independent manner. Further stimulation with NECA did not increase HIF-1{alpha} promoter activity, indicating that the A2AR-dependent increase in HIF-1{alpha} mRNA is post-transcriptional. LPS/NECA treatment also increased HIF-1{alpha} protein and DNA binding levels. Deletion of putative NF-{kappa}B-binding sites from the VEGF promoter did not affect LPS/NECA-induced VEGF promoter activity, suggesting that NF-{kappa}B is not directly involved in VEGF transcription. Taken together, these data indicate that LPS/NECA-induced VEGF expression involves transcriptional regulation of the VEGF promoter by HIF-1{alpha} through the HRE. HIF-1{alpha} is transcriptionally induced by LPS, and post-transcriptionally up-regulated in an A2AR-dependent manner.

Address correspondence to: Samuel Joseph Leibovich (leibovic{at}umdnj.edu)




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