HIF2α in the uterine stroma permits embryo invasion and luminal epithelium detachment
HIF2α in the uterine stroma permits embryo invasion and luminal epithelium detachment
复制标题
DOI：
10.1172/jci98931
复制
发表时间：
2018-07-02
影响因子：
15.9
通讯作者：
Osuga, Yutaka
中科院分区：
文献类型：
--
作者：
Matsumoto, Leona;Hirota, Yasushi;Osuga, Yutaka
虽然已经报道了低氧诱导因子2 α（HIF 2 α），一种由低氧张力诱导的主要转录因子，在胚胎植入期间在小鼠子宫中表达，但其在妊娠结局中的作用仍不清楚。本研究旨在利用转基因小鼠模型阐明子宫HIF的功能。在整个子宫中缺失Hif 2 α的小鼠（Hif 2 α-uKO小鼠）显示出由于着床失败而导致的不育。补充孕酮（P-4）和白血病抑制因子（LIF）分别恢复了Hif 2 α-uKO小鼠的蜕膜生长停滞和着床部位的异常位置，但不能挽救妊娠失败。在Hif 2 α-uKO小鼠中的组织学分析揭示了完整腔上皮的持续存在，其阻断了基质和胚胎之间的直接接触，PI 3 K-AKT通路（胚胎存活信号）的失活，以及胚胎侵袭失败。具有间质Hif 2 α缺失的小鼠（Hif 2 α-sKO小鼠）表现出不育，胚胎侵袭受损，而具有上皮Hif 2 α缺失的小鼠（Hif 2 α-sKO小鼠）表现出正常的生育力，这表明间质Hif 2 α在胚胎侵袭中的重要性。这反映在Hif 2 α-uKO基质中附着位点的膜2型金属蛋白酶（MT 2-MMP）、赖氨酰氧化酶（LOX）、VEGF和肾上腺髓质素（ADM）的表达减少，表明基质HIF 2 α调节这些介质以支持胚泡侵袭。这些发现提供了新的见解，即基质HIF 2 α通过腔上皮的分离和胚胎存活信号的激活允许滋养层侵入。
Although it has been reported that hypoxia inducible factor 2 alpha (Hif2 alpha), a major transcriptional factor inducible by low oxygen tension, is expressed in the mouse uterus during embryo implantation, its role in pregnancy outcomes remains unclear. This study aimed to clarify functions of uterine HIF using transgenic mouse models. Mice with deletion of Hif2 alpha in the whole uterus (Hif2 alpha-uKO mice) showed infertility due to implantation failure. Supplementation with progesterone (P-4) and leukemia inhibitory factor (LIF) restored decidual growth arrest and aberrant position of implantation sites in Hif2 alpha-uKO mice, respectively, but did not rescue pregnancy failure. Histological analyses in Hif2 alpha-uKO mice revealed persistence of the intact luminal epithelium, which blocked direct contact between stroma and embryo, inactivation of PI3K-AKT pathway (embryonic survival signal), and failed embryo invasion. Mice with stromal deletion of Hif2 alpha (Hif2 alpha-sKO mice) showed infertility with impaired embryo invasion and those with epithelial deletion of Hif2 alpha (Hif2 alpha-sKO mice) showed normal fertility, suggesting the importance of stromal HIF2 alpha in embryo invasion. This was reflected in reduced expression of membrane type 2 metalloproteinase (MT2-MMP), lysyl oxidase (LOX), VEGF, and adrenomedullin (ADM) in Hif2 alpha-uKO stroma at the attachment site, suggesting that stromal HIF2 alpha regulates these mediators to support blastocyst invasion. These findings provide new insight that stromal HIF2 alpha allows trophoblast invasion through detachment of the luminal epithelium and activation of an embryonic survival signal.