Transcription of the vascular endothelial growth factor gene in macrophages is regulated by liver X receptors
Transcription of the vascular endothelial growth factor gene in macrophages is regulated by liver X receptors
复制标题
DOI：
10.1074/jbc.m310587200
复制
发表时间：
2004-03-12
影响因子：
4.8
通讯作者：
Tontonoz, P
中科院分区：
文献类型：
--
作者：
Walczak, R;Joseph, SB;Tontonoz, P
巨噬细胞是伤口愈合、癌症和慢性炎症中血管生成活性的重要来源。血管内皮生长因子(VEGF)是巨噬细胞产生的一种细胞因子，在这些情况下是血管生成和新生血管的主要诱导剂。众所周知，巨噬细胞的血管内皮生长因子的表达受到低氧压和炎症信号的刺激。在这项研究中，我们提供了证据，表明Vegfa基因的表达也受到肝脏X受体(LXRs)激活的调节。在小鼠和人的原代巨噬细胞以及小鼠脂肪组织中，合成的LXR激动剂可诱导血管内皮生长因子基因的表达。LXR配体对血管内皮细胞生长因子表达的影响不依赖于缺氧诱导因子HIF-1α的激活，也不需要先前在血管内皮生长因子启动子中发现的缺氧反应元件。相反，LXR/维甲酸X受体异二聚体直接与小鼠和人类Vegfa基因启动子中的保守激素反应元件(LXRE)结合。瞬时转染实验中，LXRpha和LXRbeta均反式激活了血管内皮生长因子启动子。最后，我们证明了炎症刺激诱导的血管内皮生长因子的表达与LXRs无关，因为这些效应被保存在LXR缺失的巨噬细胞中。这些观察确定了血管内皮生长因子是LXR的靶基因，并指出了LXR在血管生物学中以前未被认识到的作用。
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.