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J. Biol. Chem., Vol. 279, Issue 11, 9905-9911, March 12, 2004

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Transcription of the Vascular Endothelial Growth Factor Gene in Macrophages Is Regulated by Liver X Receptors^*

Robert Walczak, Sean B. Joseph, Bryan A. Laffitte, Antonio Castrillo, Liming Pei, and Peter Tontonoz¶

From the Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California 90095

Macrophages are an important source of angiogenic activity in wound healing, cancer, and chronic inflammation. Vascular endothelial growth factor (VEGF), a cytokine produced by macrophages, is a primary inducer of angiogenesis and neovascularization in these contexts. VEGF expression by macrophages is known to be stimulated by low oxygen tension as well as by inflammatory signals. In this study, we provide evidence that Vegfa gene expression is also regulated by activation of liver X receptors (LXRs). VEGF mRNA was induced in response to synthetic LXR agonists in murine and human primary macrophages as well as in murine adipose tissue in vivo. The effects of LXR ligands on VEGF expression were independent of hypoxia-inducible factor HIF-1 activation and did not require the previously characterized hypoxia response element in the VEGF promoter. Rather, LXR/retinoid X receptor heterodimers bound directly to a conserved hormone response element (LXRE) in the promoter of the murine and human Vegfa genes. Both LXR and LXR transactivated the VEGF promoter in transient transfection assays. Finally, we show that induction of VEGF expression by inflammatory stimuli was independent of LXRs, because these effects were preserved in LXR null macrophages. These observations identify VEGF as an LXR target gene and point to a previously unrecognized role for LXRs in vascular biology.

Received for publication, September 24, 2003 , and in revised form, December 24, 2003.

^* This work was supported by National Institutes of Health Grant HL-66088. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Assistant investigator of the Howard Hughes Medical Institute at the University of California, Los Angeles. To whom correspondence should be addressed: Howard Hughes Medical Inst., UCLA, Box 951662, Los Angeles, CA 90095-1662. Tel.: 310-206-4546; Fax: 310-267-0382; E-mail: ptontonoz{at}mednet.ucla.edu.

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