Transcription of the vascular endothelial growth factor gene in macrophages is regulated by liver X receptors.
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-1alpha 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 LXRalpha and LXRbeta 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.
Walczak
Robert
R
Howard Hughes Medical Institute, University of California, Los Angeles, California 90095-1662, USA.
Joseph
Sean B
SB
Laffitte
Bryan A
BA
Castrillo
Antonio
A
Pei
Liming
L
Tontonoz
Peter
P
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004268:DNA-Binding Proteins; D019281:Dimerization; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007249:Inflammation; D008024:Ligands; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D010100:Oxygen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism
D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D012313:RNA; D010100:Oxygen