Lipoxin A4 interferes with embryo implantation via suppression of epithelial-mesenchymal transition
Lipoxin A4 interferes with embryo implantation via suppression of epithelial-mesenchymal transition
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脂氧素 A4 通过抑制上皮间质转化干扰胚胎植入
DOI：
10.1111/aji.13107
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发表时间：
2019
影响因子：
3.6
通讯作者：
Huang Yinping
中科院分区：
文献类型：
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作者：
Xu Zhangye;Zhao Shenzhi;Zhou Tong;Liao Tingting;Huang Xianping;Xiang Huiqiu;Zhang Qiong;Huang Yanjun;Lin Feng;Ye Duyun;Huang Yinping
目的探讨脂氧素A4(LXA4)是否通过抑制上皮-间充质转化(EMT)而干扰胚胎着床。方法建立LXA4阻断胚胎着床的小鼠模型，检测EMT指标，证实LXA4抑制EMT可能是其干预胚胎着床的机制之一。采用逆转录-聚合酶链式反应和实时荧光定量RT-PCR法检测整合素连接蛋白(ILK)、N-甲酰基肽受体2(FPR2)、血管内皮生长因子、基质金属蛋白酶(MMPs)、Akt、Gsk3β、核因子-ĸB、Twist、波形蛋白、纤维连接蛋白和β-catenin基因的表达，免疫组织化学和Western blotting检测蛋白表达，明胶酶谱检测MMPs活性，脑桥蓝试验评价着床情况。LXA4对胚胎着床有时间和剂量依赖效应。受精后0.5d是LXA4阻断胚胎着床的最有效时间。(2)LXA4抑制β-连环蛋白的表达，下调波形蛋白、纤维连接蛋白、TWIST、NF-κB、AKT和β的表达；(C)LXA4上调FPR2的表达，下调ILK的表达；FPR2过表达对ILK的表达有抑制作用。
ProblemTo test whether lipoxin A4 (LXA4) interferes with embryo implantation via suppression of epithelial‐mesenchymal transition (EMT).Method of studyWe developed a mouse model of LXA4 blocking embryo implantation and detected the indicators of EMT to confirm that LXA4 inhibits EMT might be a mechanism of interfering with the embryo implantation. We detected integrin‐linked kinase (ILK), N‐formylpeptide receptor 2 (FPR2), vascular endothelial growth factor, matrix metalloproteinases (MMPs), Akt, GSK3β, NF‐ĸB, twist, vimentin, fibronectin, and β‐catenin mRNA expression using reverse transcriptase‐polymerase chain reaction (RT‐PCR) and real‐time RT‐PCR; localized protein expression using immunohistochemistry and Western blotting assay; MMPs activity assay by gelatin zymography; and the status of implantation in pregnant animals assessed by pontamine blue reaction test.ResultsPreimplantation administration of LXA4 resulted in implantation failure. LXA4 has a time‐ and dose‐dependent effect on embryo implantation. Day 0.5 after fertilization is the most effective time to use LXA4 to block embryo implantation. (a) LXA4 reduced endometrial stroma edema; (b) LXA4 inhibited the activity of MMP9 and significantly upregulated the expression of β‐catenin, and downregulated the expression of vimentin, fibronectin, twist, NF‐κB, Akt, and Gsk‐3β in the endometrium and TEV‐1 cells; (c) LXA4 upregulated the expression of FPR2, and downregulated the expression of ILK; FPR2‐overexpressing had an inhibitory effect on ILK in TEV‐1 cells.ConclusionLXA4 inhibits EMT which attenuates ILK action by enhancing FPR2; therefore, this might be a mechanism of interfering with embryo implantation.