Transcriptional activation of hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis through VEGF and S100A8
Transcriptional activation of hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis through VEGF and S100A8
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DOI：
10.1073/pnas.1320243111
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发表时间：
2014-02-18
影响因子：
11.1
通讯作者：
Brown, J. Martin
中科院分区：
文献类型：
--
作者：
Ahn, G-One;Seita, Jun;Brown, J. Martin
新出现的证据表明，髓样细胞是通过分泌各种血管生成因子促进新血管形成所必需的。鉴于缺氧诱导因子（HIF）是血管生成的关键调节因子，我们质疑髓样细胞中的HIF是否也在促进血管生成中发挥作用。为了解决这个问题，我们产生了一个独特的骨髓特异性敲除小鼠株靶向HIF通路使用人S100 A8作为骨髓特异性启动子。我们观察到，突变小鼠的骨髓细胞中的HIF-1是转录激活（通过删除冯希佩尔-林道基因）导致红斑，增强血管新生的基质胶塞，并增加生产的血管内皮生长因子（VEGF）在骨髓中，所有这些都被完全废除的基因或药理学失活的HIF-1。我们进一步发现单核细胞是产生VEGF和S100 A8蛋白的主要效应子，其驱动基质胶中的新血管形成。此外，通过使用后肢缺血的小鼠模型，我们观察到肌肉内注射HIF-1激活的单核细胞的小鼠的血流量显著改善。因此，这项研究表明，骨髓细胞中的HIF-1激活通过VEGF和S100 A8促进血管生成，这可能成为治疗血管缺陷疾病的有吸引力的治疗策略。
Emerging evidence indicates that myeloid cells are essential for promoting new blood vessel formation by secreting various angiogenic factors. Given that hypoxia-inducible factor (HIF) is a critical regulator for angiogenesis, we questioned whether HIF in myeloid cells also plays a role in promoting angiogenesis. To address this question, we generated a unique strain of myeloid-specific knockout mice targeting HIF pathways using human S100A8 as a myeloid-specific promoter. We observed that mutant mice where HIF-1 is transcriptionally activated in myeloid cells (by deletion of the von Hippel-Lindau gene) resulted in erythema, enhanced neovascularization in matrigel plugs, and increased production of vascular endothelial growth factor (VEGF) in the bone marrow, all of which were completely abrogated by either genetic or pharmacological inactivation of HIF-1. We further found that monocytes were the major effector producing VEGF and S100A8 proteins driving neovascularization in matrigel. Moreover, by using a mouse model of hindlimb ischemia we observed significantly improved blood flow in mice intramuscularly injected with HIF-1-activated monocytes. This study therefore demonstrates that HIF-1 activation in myeloid cells promotes angiogenesis through VEGF and S100A8 and that this may become an attractive therapeutic strategy to treat diseases with vascular defects.