Winn Virginia D, Gormley Matthew, Paquet Agnes C, Kjaer-Sorensen Kasper, Kramer Anita, Rumer Kristen K, Haimov-Kochman Ronit, Yeh Ru-Fang, Overgaard Michael T, Varki Ajit, Oxvig Claus, Fisher Susan J
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, San Francisco, California 94143, USA.
Endocrinology. 2009 Jan;150(1):452-62. doi: 10.1210/en.2008-0990. Epub 2008 Sep 25.
Preeclampsia (PE), which affects 4-8% of human pregnancies, causes significant maternal and neonatal morbidity and mortality. Within the basal plate, placental cytotrophoblasts (CTBs) of fetal origin invade the uterus and extensively remodel the maternal vasculature. In PE, CTB invasion is often shallow, and vascular remodeling is rudimentary. To better understand possible causes, we conducted a global analysis of gene expression at the maternal-fetal interface in placental samples from women with PE (n = 12; 24-36 wk) vs. samples from women who delivered due to preterm labor with no evidence of infection (n = 11; 24-36 wk), a condition that our previous work showed is associated with normal CTB invasion. Using the HG-U133A&B Affymetrix GeneChip platform, and statistical significance set at log odds-ratio of B >0, 55 genes were differentially expressed in PE. They encoded proteins previously associated with PE [e.g. Flt-1 (vascular endothelial growth factor receptor-1), leptin, CRH, and inhibin] and novel molecules [e.g. sialic acid binding Ig-like lectin 6 (Siglec-6), a potential leptin receptor, and pappalysin-2 (PAPP-A2), a protease that cleaves IGF-binding proteins]. We used quantitative PCR to validate the expression patterns of a subset of the genes. At the protein level, we confirmed PE-related changes in the expression of Siglec-6 and PAPP-A2, which localized to invasive CTBs and syncytiotrophoblasts. Notably, Siglec-6 placental expression is uniquely human, as is spontaneous PE. The functional significance of these novel observations may provide new insights into the pathogenesis of PE, and assaying the circulating levels of these proteins could have clinical utility for predicting and/or diagnosing PE.
子痫前期（PE）影响4%-8%的人类妊娠，会导致严重的母婴发病和死亡。在基底板内，源自胎儿的胎盘细胞滋养层细胞（CTB）侵入子宫并广泛重塑母体血管系统。在子痫前期中，CTB的侵入通常较浅，血管重塑也很不完善。为了更好地理解可能的原因，我们对患有子痫前期的女性（n = 12；24-36周）的胎盘样本与因早产分娩且无感染迹象的女性（n = 11；24-36周）的胎盘样本进行了母胎界面基因表达的全局分析，我们之前的研究表明，后一种情况与正常的CTB侵入有关。使用HG-U133A&B Affymetrix基因芯片平台，并将统计学显著性设定为B>0的对数优势比，在子痫前期中有55个基因差异表达。它们编码的蛋白质先前已与子痫前期相关[例如Flt-1（血管内皮生长因子受体-1）、瘦素、促肾上腺皮质激素释放激素和抑制素]以及新分子[例如唾液酸结合免疫球蛋白样凝集素6（Siglec-6），一种潜在的瘦素受体，以及妊娠相关血浆蛋白A2（PAPP-A2），一种裂解胰岛素样生长因子结合蛋白的蛋白酶]。我们使用定量PCR来验证一部分基因的表达模式。在蛋白质水平上，我们证实了Siglec-6和PAPP-A2表达的子痫前期相关变化，它们定位于侵入性CTB和合体滋养层细胞。值得注意的是，Siglec-6在胎盘中的表达是人类独有的，子痫前期也是如此。这些新发现的功能意义可能为子痫前期的发病机制提供新的见解，检测这些蛋白质的循环水平可能对预测和/或诊断子痫前期具有临床应用价值。
