Abstract
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.
Highlights
Vascular endothelial growth factor (VEGF),1 known as vascular permeability factor, is the founding member of a family of closely related cytokines that exert critical functions in angiogenesis and lymphangiogenesis
We examined the ability of synthetic liver X receptors (LXRs) agonists to regulate expression of Vegfa gene in primary murine and human macrophages
As VEGF expression is known to be responsive to a number of signaling pathways including factors present in serum, we investigated the regulation of VEGF expression in macrophages cultured in serum-free medium
Summary
Vascular endothelial growth factor (VEGF), known as vascular permeability factor, is the founding member of a family of closely related cytokines that exert critical functions in angiogenesis and lymphangiogenesis. Cell differentiation status plays an important role in the regulation of VEGF expression. In liver, where LXR␣ is very highly expressed, this receptor appears to play a important role in the control of genes linked to cholesterol and fatty acid metabolism such as Srebp-1c and Cyp7a1 [24, 25]. In macrophages, where both receptors are abundantly expressed, target genes such as Abca, Abcg, and apoE are equivalently induced by both receptors [26, 27]. These observations point to a previously unrecognized role for LXRs in vascular biology
Full Text
Topics from this Paper
Vascular Endothelial Growth Factor Expression In Macrophages
Liver X Receptors Agonists
Full Text PDF PubMed Scopus
Liver X Receptors
Vascular Endothelial Growth Factor
+ Show 5 more
Create a personalized feed of these topics
Get StartedTalk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Similar Papers
Journal of Biological Chemistry
Sep 1, 2000
Journal of Biological Chemistry
Nov 1, 2001
Journal of Biological Chemistry
Dec 1, 2001
Journal of Lipid Research
Apr 1, 2004
Journal of Biological Chemistry
Jan 1, 1999
Journal of Biological Chemistry
Oct 1, 2006
Journal of Hepatology
May 1, 2001
Journal of Biological Chemistry
Jul 1, 2000
Fertility and Sterility
Mar 1, 2012
Journal of Biological Chemistry
Aug 1, 2002
Journal of Lipid Research
Aug 1, 2004
Journal of Biological Chemistry
Feb 1, 2007
Journal of Biological Chemistry
Mar 1, 2009
Journal of Investigative Dermatology
May 1, 2008
Journal of Biological Chemistry
Apr 1, 2003
Journal of Biological Chemistry
Journal of Biological Chemistry
Dec 1, 2023
Journal of Biological Chemistry
Dec 1, 2023
Journal of Biological Chemistry
Nov 1, 2023
Journal of Biological Chemistry
Nov 1, 2023
Journal of Biological Chemistry
Nov 1, 2023
Journal of Biological Chemistry
Nov 1, 2023
Journal of Biological Chemistry
Nov 1, 2023
Journal of Biological Chemistry
Nov 1, 2023
Journal of Biological Chemistry
Nov 1, 2023
Journal of Biological Chemistry
Nov 1, 2023