VEGF Receptor 1 Promotes Hypoxia-Induced Hematopoietic Progenitor Proliferation and Differentiation.
VEGF Receptor 1 Promotes Hypoxia-Induced Hematopoietic Progenitor Proliferation and Differentiation.
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DOI：
10.3389/fimmu.2022.882484
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
虽然众所周知，缺氧会引发释放的细胞炎症，但缺氧条件下过度细胞炎症的机制尚不清楚。我们观察到在缺氧条件下小鼠造血干细胞和祖细胞（HSPC）的增殖增加，HSPC是炎症性白细胞的前体。因此，暴露于缺氧条件下的人HSPC的转录组学分析揭示了参与祖细胞增殖和分化的基因的表达升高。此外，小鼠骨髓细胞表达大量血管内皮生长因子（VEGF），HSPC在缺氧条件下升高VEGF受体1（VEGFr 1）及其靶基因。与此一致，体内和体外VEGFr 1阻断降低了HSPC增殖并减轻了炎症。计算机模拟和ChIP实验证明HIF-1α与VEGFR 1的启动子区结合。相应地，HIF 1a沉默降低了HSPC中VEGFr 1的表达并减少了其增殖。这些结果表明，HSPC中的VEGF信号传导是其在缺氧诱导的炎症中增殖和分化的重要介质，并且代表了预防缺氧相关疾病中异常炎症的潜在治疗靶点。
Although it is well known that hypoxia incites unleashed cellular inflammation, the mechanisms of exaggerated cellular inflammation in hypoxic conditions are not known. We observed augmented proliferation of hematopoietic stem and progenitor cells (HSPC), precursors of inflammatory leukocytes, in mice under hypoxia. Consistently, a transcriptomic analysis of human HSPC exposed to hypoxic conditions revealed elevated expression of genes involved in progenitor proliferation and differentiation. Additionally, bone marrow cells in mice expressed high amount of vascular endothelial growth factor (VEGF), and HSPC elevated VEGF receptor 1 (VEGFr1) and its target genes in hypoxic conditions. In line with this, VEGFr1 blockade in vivo and in vitro decreased HSPC proliferation and attenuated inflammation. In silico and ChIP experiments demonstrated that HIF-1α binds to the promoter region of VEGFR1. Correspondingly, HIF1a silencing decreased VEGFr1 expression in HSPC and diminished their proliferation. These results indicate that VEGF signaling in HSPC is an important mediator of their proliferation and differentiation in hypoxia-induced inflammation and represents a potential therapeutic target to prevent aberrant inflammation in hypoxia-associated diseases.
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影响因子：
20.3
作者：
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通讯作者：
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14.8
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Benita Y;Kikuchi H;Smith AD;Zhang MQ;Chung DC;Xavier RJ
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