Analysis of Fertility-Related Soluble Mediators in Human Uterine Fluid Identifies VEGF as a Key Regulator of Embryo Implantation
Analysis of Fertility-Related Soluble Mediators in Human Uterine Fluid Identifies VEGF as a Key Regulator of Embryo Implantation
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DOI：
10.1210/en.2011-1248
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发表时间：
2011-12-01
期刊：
影响因子：
4.8
通讯作者：
Salamonsen, L. A.
中科院分区：
文献类型：
--
作者：
Hannan, N. J.;Paiva, P.;Salamonsen, L. A.
胚胎植入需要通过局部产生的可溶性介质在接受子宫内膜和活化的囊胚之间进行同步对话。在月经周期的分泌中期 (MS) 阶段，子宫腔内腺体分泌增加，其中含有重要的介质，可调节子宫内膜并在着床期间支持受孕。本研究首先旨在确定周期中增殖期（MP；非接受期）和 MS（接受期）阶段的生育女性以及 MS 期不明原因不孕女性的人类子宫液中的生长因子和细胞因子谱。第二个目的是确定子宫内膜分泌物对于胚胎植入的重要功能。使用 Luminex 定量分析对子宫液进行分析，结果显示存在超过 30 种细胞因子和生长因子，其中 8 种[血小板衍生生长因子-AA、TNF-B、可溶性 IL-2 受体-A、Fms 样酪氨酸激酶 3 配体、可溶性 CD40 配体、IL-7、干扰素-A2 和趋化因子（C-X-C 基序）配体 1-3] 以前在人类子宫液中是未知的。对可育 MP、MS 和不育 MS 队列的比较显示，与可育女性相比，不明原因不孕女性在 MS 阶段子宫液中血管内皮生长因子 (VEGF) 水平显着降低。功能研究表明，用来自可育女性的 MS 期子宫液或重组人 VEGF 培养小鼠胚胎可显着增强囊胚的生长。此外，用子宫液或重组人VEGF-A处理人子宫内膜上皮细胞显着增加子宫内膜上皮细胞粘附。综上所述，我们的数据支持子宫内膜分泌物（包括 VEGF）在着床过程中发挥重要作用的概念。识别人类子宫液中的可溶性介质及其在植入过程中的作用，可以深入了解对于建立妊娠、生育标志物和不孕不育治疗方案至关重要的相互作用。 （内分泌学152：4948-4956，2011）
Embryo implantation requires synchronized dialogue between the receptive endometrium and activated blastocyst via locally produced soluble mediators. During the midsecretory (MS) phase of the menstrual cycle, increased glandular secretion into the uterine lumen contains important mediators that modulate the endometrium and support the conceptus during implantation. This study aimed first to identify the growth factor and cytokine profile of human uterine fluid from fertile women during the midproliferative (MP; nonreceptive) and MS (receptive) phases of the cycle, and from women with unexplained infertility during the MS phase. The second aim was to determine important functions of endometrial secretions for embryo implantation. Analysis of uterine fluid using quantitative Luminex assays revealed the presence of over 30 cytokines and growth factors, of which eight [platelet-derived growth factor-AA, TNF-B, soluble IL-2 receptor-A, Fms-like tyrosine kinase 3 ligand, soluble CD40 ligand, IL-7, interferon-A2, and chemokine (C-X-C motif) ligand 1-3] were previously unknown in human uterine fluid. Comparison of the fertile MP, MS, and infertile MS cohorts revealed vascular endothelial growth factor (VEGF) levels are significantly reduced in uterine fluid during the MS phase in women with unexplained infertility compared with fertile women. Functional studies demonstrated that culturing mouse embryos with either MS-phase uterine fluid from fertile women or recombinant human VEGF significantly enhanced blastocyst outgrowth. Furthermore, treatment of human endometrial epithelial cells with uterine fluid or recombinant human VEGF-A significantly increased endometrial epithelial cell adhesion. Taken together, our data support the concept that endometrial secretions, including VEGF, play important roles during implantation. Identifying the soluble mediators in human uterine fluid and their actions during implantation provides insight into interactions essential for establishing pregnancy, fertility markers, and infertility treatment options. (Endocrinology 152: 4948-4956, 2011)