血管内皮生长因子
分子生物学
一氧化氮合酶
脂多糖
缺氧(环境)
下调和上调
生物
转染
一氧化氮
血管内皮生长因子A
基因表达
转录因子
化学
细胞培养
癌症研究
免疫学
内分泌学
基因
血管内皮生长因子受体
生物化学
有机化学
氧气
遗传学
作者
Madhuri Ramanathan,Avi Giladi,Samuel Leibovich
标识
DOI:10.1177/153537020322800608
摘要
Vascular endothelial growth factor (VEGF) expression in murine peritoneal macrophages is strongly upregulated by hypoxia via transcriptional and posttranscriptional mechanisms. Interferon-gamma (IFN-gamma) with Escherichia coli lipopolysaccharide (LPS) also upregulates expression of VEGF, as well as of the inducible nitric oxide synthase (iNOS). Hypoxia (1% O(2)) upregulates VEGF expression in macrophages from both wild-type and iNOS knockout mice, indicating that hypoxic upregulation of VEGF is independent of iNOS. However, the iNOS inhibitor aminoguanidine (AG) decreases the VEGF expression induced by LPS/IFN-gamma, indicating an important role for NO. NO-dependent induction of VEGF is strongly dependent on cell density. LPS/IFN-gamma treatment induces minimal VEGF protein expression in macrophages cultured at low cell densities (<0.25 x 10(6) cells/cm(2)); at higher cell densities (>0.25 x 10(6) cells/cm(2)) that lead to conditions of pericellular hypoxia, however, induction of VEGF expression was strong. Transient transfection of RAW 264.7 cells with luciferase reporter constructs of the murine VEGF promoter indicates that both hypoxia and LPS/IFN-gamma independently induce VEGF promoter activity, irrespective of cell density. Although LPS/IFN-gamma treatment induces transcriptional activation of the VEGF promoter, significant levels of VEGF protein are only expressed by cells at high density under conditions of pericellular hypoxia. This suggests an important regulatory role for hypoxia at the posttranscriptional level. Deletion analysis of the VEGF promoter shows that the hypoxia response element region and its immediate flanking sequences are essential for both hypoxia and LPS/IFN-gamma-induced VEGF promoter activation.
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