Opposing roles for HIF-1α and HIF-2α in the regulation of angiogenesis by mononuclear phagocytes
Opposing roles for HIF-1α and HIF-2α in the regulation of angiogenesis by mononuclear phagocytes
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DOI：
10.1182/blood-2010-01-261792
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发表时间：
2011-01-06
期刊：
影响因子：
20.3
通讯作者：
Marsh, Clay B.
中科院分区：
文献类型：
--
作者：
Eubank, Tim D.;Roda, Julie M.;Marsh, Clay B.
巨噬细胞通过分泌促血管生成分子血管内皮生长因子（VEGF）促进肿瘤生长。我们之前观察到，用细胞因子粒细胞巨噬细胞集落刺激因子 (GM-CSF) 处理的单核细胞会产生可溶形式的 VEGF 受体-1 (sVEGFR-1)，从而中和 VEGF 生物活性。 VEGF和VEGFR-1启动子均含有缺氧调节元件，在缺氧条件下结合缺氧诱导因子（HIF）转录因子。基于这一观察，我们检查了在不同 O(2) 浓度下培养的单核细胞的 VEGF 和 sVEGFR-1 产量。从GM-CSF处理的单核细胞中观察到的sVEGFR-1产生量随着O(2)水平的降低而增加。该 sVEGFR-1 具有生物活性并隔离 VEGF。为了评估 HIF 在 sVEGFR-1 产生中的作用，我们使用了 HIF-1 α 基因缺失的巨噬细胞。与HIF-1α(+/+)巨噬细胞相比，在缺氧条件下与GM-CSF一起培养的HIF-1α(-/-)巨噬细胞分泌的VEGF量减少，而sVEGFR-1分泌不受影响。相反，siRNA介导的HIF-2α敲低抑制了响应GMCSF和低O(2)的sVEGFR-1的产生，而VEGF的产生不受影响。这些研究表明，通常被认为促进血管生成的缺氧可以在富含 GM-CSF 的环境中诱导巨噬细胞的抗血管生成行为。此外，这些结果表明 HIF-1 α 和 HIF-2 α 在缺氧巨噬细胞中具有特定且独立的作用。 （血。2011；117（1）：323-332）
Macrophages contribute to tumor growth through the secretion of the proangiogenic molecule vascular endothelial growth factor (VEGF). We previously observed that monocytes treated with the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) produce a soluble form of the VEGF receptor-1 (sVEGFR-1), which neutralizes VEGF biologic activity. The VEGF and VEGFR-1 promoters both contain a hypoxia regulatory element, which binds the hypoxia-inducible factor (HIF) transcription factors under hypoxic conditions. Based on this observation, we examined VEGF and sVEGFR-1 production from monocytes cultured at various O(2) concentrations. The amount of sVEGFR-1 production observed from GM-CSF-treated monocytes increased with decreasing levels of O(2). This sVEGFR-1 was biologically active and sequestered VEGF. To evaluate the role of the HIFs in sVEGFR-1 production, we used macrophages with a genetic deletion of HIF-1 alpha. HIF-1 alpha(-/-) macrophages cultured with GM-CSF at hypoxia secreted diminished amounts of VEGF compared with HIF-1 alpha(+/+) macrophages, whereas sVEGFR-1 secretion was unaffected. In contrast, siRNA-mediated knockdown of HIF-2 alpha inhibited the production of sVEGFR-1 in response to GMCSF and low O(2), whereas VEGF production was unaffected. These studies suggest that hypoxia, generally thought to promote angiogenesis, can induce antiangiogenic behavior from macrophages within a GM-CSF-rich environment. Furthermore, these results suggest specific and independent roles for HIF-1 alpha and HIF-2 alpha in hypoxic macrophages. (Blood. 2011;117(1):323-332)