Bioinformatics approach reveals evidence for impaired endometrial maturation before and during early pregnancy in women who developed preeclampsia.
Bioinformatics approach reveals evidence for impaired endometrial maturation before and during early pregnancy in women who developed preeclampsia.
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DOI：
10.1161/hypertensionaha.114.04481
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发表时间：
2015-02
期刊：
影响因子：
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通讯作者：
Conrad KP
中科院分区：
文献类型：
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作者：
Rabaglino MB;Post Uiterweer ED;Jeyabalan A;Hogge WA;Conrad KP
妊娠早期绒毛外滋养细胞(EVT)对子宫的侵袭受损与子痫前期的发生有关，子痫前期是人类妊娠的一种潜在的致命性疾病。然而，EVT功能障碍的原因尚不清楚，这是因为患先兆子痫的妇女几乎无法接触到早期的胎盘和子宫组织，也没有自发发生这种疾病的动物模型。因此，子痫前期子宫内膜成熟不足或缺陷(“蜕膜化”)可能影响EVT侵袭的可能性仍未被探讨。使用生物信息学方法，我们验证了这一假设，从11.5周的绒毛样本(CVS)中识别出396个差异表达基因(DEG)，这些基因来自妊娠约11.5周的妇女，她们在6个月后出现严重的先兆子痫症状，与正常妊娠的CVS相比。根据其他微阵列数据(p=4.7x10−14)，与植入前后正常子宫内膜成熟的不同阶段相关的大量(154或40%)DEG与DEG重叠。其中116例(75%)与无腔静脉血栓形成的正常蜕膜化子宫内膜，即分泌晚期子宫内膜和输卵管异位妊娠子宫内膜重叠(p=4.2×10−9)。最后，在与正常子宫内膜成熟相关的微阵列数据集中，112例(73%)DEG发生了相反方向的改变(p=0.0001)，其中16例DEG在蜕膜(相对于外周血)中上调，而后者在患先兆子痫的CVS中下调(p<；0.0001)。综上所述，这些结果提示分泌期和妊娠早期子宫内膜和蜕膜自然杀伤细胞成熟不足或缺陷先于先兆子痫的发生。
Impaired uterine invasion by extravillous trophoblast (EVT) in early gestation is implicated in the genesis of preeclampsia, a potentially lethal malady of human pregnancy. However, reasons for EVT dysfunction remain unclear due to virtual inaccessibility of early placental and uterine tissues from women who develop preeclampsia, and the absence of animal models in which the disease spontaneously occurs. Consequently, the possibility that deficient or defective maturation of the endometrium (“decidualization”) may compromise EVT invasion in preeclampsia remains unexplored. Using a bioinformatics approach, we tested this hypothesis identifying 396 differentially expressed genes (DEG) in chorionic villous samples (CVS) from women at ~11.5 gestational weeks who developed severe preeclampsia symptoms 6-months later compared to CVS from normal pregnancies. A large number, 154 or 40%, overlapped with DEG associated with various stages of normal endometrial maturation before and after implantation as identified by other microarray datasets (p=4.7×10−14). 116 of the 154 DEG or 75%, overlapped with DEG associated with normal decidualization in the absence of EVT, i.e., late-secretory endometrium and endometrium from tubal ectopic pregnancy (p=4.2×10−9). Finally, 112 of these 154 DEG or 73% changed in the opposite direction in microarray datasets related to normal endometrial maturation (p=0.01) including 16 DEG up-regulated in decidual (relative to peripheral blood) Natural Killer cells that were down-regulated in CVS from women who developed preeclampsia (p<0.0001). Taken together, these results suggest that insufficient or defective maturation of endometrium and decidual Natural Killer cells during the secretory phase and early pregnancy preceded the development of preeclampsia.