Preeclampsia (PE) is a placental disorder caused by endothelial dysfunction via trophoblast inadequate invasion activity. Adrenomedullin (ADM) and ADM2 are multifunctional peptides that can support vascular activity and placental growth. However, correlation between ADMs and trophoblast functions is currently unclear. The objective of this study was to analyze changes in expression of ADMs in placenta and HTR-8/SVneo trophoblast cells under hypoxia and their effects on invasion activity of trophoblast cells and expression of HLA-G. In placental tissues of PE, expression levels of ADM and HLA-G were significantly increased (P < 0.05) whereas expression of ADM2 was decreased compared to that in normal term placenta. Under hypoxia, expression levels of ADM, ADM2, and HLA-G and invasion ability of trophoblast cells were increased in hypoxia-inducible factor-1 (HIF-1α)- dependent manner (P < 0.05). Treatment with ADMs agonists reduced HIF-1α activity whereas enhanced invasion ability under hypoxia. However, they were not changed after cotreatment of ADMs and HIF-1α inhibitor, YC-1, although expression levels of invasion-related genes MMP2, MMP9, and Rac1 were altered (P < 0.05). ADMs also increased HLA-G expression under normoxia whereasADM2 or cotreatment of ADMs under hypoxia attenuated HLA-G expression (P < 0.05). Our findings demonstrate that altered expression of ADMs plays a critical role in placental physiology, especially in trophoblast invasion and immune-modulation under hypoxia.

中文翻译：

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缺氧改变 ADM 和 ADM2 的表达调节滋养层的迁移和 HLA-G 表达†

先兆子痫（PE）是一种胎盘疾病，由内皮功能障碍通过滋养细胞侵袭活性不足引起。肾上腺髓质素 (ADM) 和 ADM2 是多功能肽，可以支持血管活动和胎盘生长。然而，ADMs 与滋养层功能之间的相关性目前尚不清楚。本研究的目的是分析缺氧条件下胎盘和HTR-8/SVneo滋养层细胞中ADMs的表达变化及其对滋养层细胞侵袭活性和HLA-G表达的影响。PE胎盘组织中ADM和HLA-G的表达水平显着升高（P < 0.05) 而 ADM2 的表达与正常足月胎盘相比有所降低。缺氧条件下，ADM、ADM2、HLA-G的表达水平和滋养层细胞的侵袭能力以缺氧诱导因子-1（HIF-1α）依赖的方式增加（P  < 0.05）。用 ADMs 激动剂处理降低 HIF-1α 活性，而增强缺氧条件下的侵袭能力。然而，尽管侵袭相关基因MMP2、MMP9和Rac1的表达水平发生了改变（P  < 0.05），但在ADMs和HIF-1α抑制剂YC-1共同处理后，它们没有改变。ADMs 在常氧条件下也增加 HLA-G 表达，而 ADM2 或在缺氧条件下共同处理 ADMs 减弱 HLA-G 表达（P < 0.05)。我们的研究结果表明，ADM 表达的改变在胎盘生理学中起着关键作用，尤其是在缺氧条件下的滋养细胞侵袭和免疫调节中。