Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK.
Mol Hum Reprod. 2010 Apr;16(4):273-85. doi: 10.1093/molehr/gap108. Epub 2009 Dec 14.
Pregnancy is dependent upon the endometrium acquiring a receptive phenotype that facilitates apposition, adhesion and invasion of a developmentally competent embryo. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry of mid-secretory endometrial biopsies revealed a 28 kDa protein peak that discriminated highly between samples obtained from women with recurrent implantation failure and fertile controls. Subsequent tandem mass spectroscopy unambiguously identified this peak as apolipoprotein A-I (apoA-I), a potent anti-inflammatory molecule. Total endometrial apoA-I levels were, however, comparable between the study and control group. Moreover, endometrial apoA-I mRNA expression was not cycle-dependent although there was partial loss of apoA-I immunoreactivity in luminal and glandular epithelium in mid-secretory compared with proliferative endometrial samples. Because of its putative anti-implantation properties, we examined whether endometrial apoA-I expression is regulated by embryonic signals. Human chorionic gonadotrophin (hCG) strongly inhibited apoA-I expression in differentiating explant cultures but not when established from eutopic endometrium from patients with endometriosis. Pelvic endometriosis was associated with elevated apoA-I mRNA levels, increased secretion by differentiating eutopic endometrial explant cultures and lack of hCG-dependent down-regulation. To corroborate these observations, we examined endometrial apoA-I expression and its regulation by hCG in a non-human primate model of endometriosis. As in humans, hCG strongly inhibited endometrial apoA-I mRNA expression in disease-free baboons, but this response was entirely lost upon induction of pelvic endometriosis. Together, these observations indicate that perturbations in endometrial apoA-I expression, modification or regulation by paracrine embryonic signals play a major role in implantation failure and infertility.
妊娠依赖于子宫内膜获得接受表型，从而促进具有发育能力的胚胎的附着、黏附和侵袭。对中分泌期子宫内膜活检进行表面增强激光解吸/电离飞行时间质谱分析显示，在反复着床失败和有生育能力的对照组妇女的样本中，有一个 28 kDa 的蛋白质峰具有高度鉴别能力。随后的串联质谱分析明确鉴定该峰为载脂蛋白 A-I（apoA-I），这是一种有效的抗炎分子。然而，研究组和对照组之间的总子宫内膜 apoA-I 水平相当。此外，尽管在中分泌期与增生期子宫内膜样本相比，腔上皮和腺上皮中的 apoA-I 免疫反应性部分丧失，但子宫内膜 apoA-I mRNA 表达无周期依赖性。由于其潜在的抗着床特性，我们研究了胚胎信号是否调节子宫内膜 apoA-I 表达。人绒毛膜促性腺激素（hCG）强烈抑制分化培养物中 apoA-I 的表达，但对来源于子宫内膜异位症患者的在位子宫内膜建立的培养物则无此作用。盆腔子宫内膜异位症与 apoA-I mRNA 水平升高、分化的在位子宫内膜外植体培养物的分泌增加以及 hCG 依赖性下调缺失相关。为了证实这些观察结果，我们在子宫内膜异位症的非人类灵长类动物模型中检查了子宫内膜 apoA-I 表达及其对 hCG 的调节。与人类一样，hCG 强烈抑制无疾病的狒狒的子宫内膜 apoA-I mRNA 表达，但在诱导盆腔子宫内膜异位症后，这种反应完全丧失。总之，这些观察结果表明，子宫内膜 apoA-I 表达的干扰、修饰或旁分泌胚胎信号的调节在着床失败和不孕中起着重要作用。
