INRS-Institut Armand-Frappier, 531 boulevard des Prairies, Laval, QC, H7V 1B7, Canada; BioMed Research Centre, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC, H3C 3P8, Canada; Center for Interdisciplinary Research on Well-Being, Health, Society and Environment (CINBIOSE), Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC, H3C 3P8, Canada.
Department of Gynecology Obstetrics, Faculty of Medicine, Université de Genève, 1 rue Michel Servet, 1205, Geneva, Switzerland.
Placenta. 2018 Dec;72-73:62-73. doi: 10.1016/j.placenta.2018.10.007. Epub 2018 Oct 30.
Between 2 and 10% of pregnant women are treated with selective serotonin-reuptake inhibitors (SSRIs) for depression. The extravillous trophoblasts (evTBs), which migrate and invade maternal tissues, are crucial for embryo implantation and remodeling of maternal spiral arteries. Poor migration/invasion of evTBs can cause serious pregnancy complications, yet the effects of SSRIs on these processes has never been studied. To determine the effects of five SSRIs (fluoxetine, norfluoxetine, citalopram, sertraline and venlafaxine) on migration/invasion, we used JEG-3 and HIPEC cells as evTB models.
Cells were treated with increasing concentrations (0.03-10 μM) of SSRIs. Cell proliferation was monitored using an impedance-based system and cell cycle by flow cytometry. Migration was determined using a scratch test, and metalloproteinase (MMP) activities, by zymography. Invasion markers were determined by RT-qPCR.
Fluoxetine and sertraline (10 μM) significantly decreased cell proliferation by 94% and by 100%, respectively, in JEG-3 cells, and by 58.6% and 100%, respectively, in HIPEC cells. Norfluoxetine increased MMP-9 activity in JEG-3 cells by 2.0% at 0.03 μM and by 43.9% at 3 μM, but decreased MMP-9 activity in HIPEC cells by 63.7% at 3 μM. Sertraline at 0.03 μM increased mRNA level of TIMP-1 in JEG-3 cells by 36% and that of ADAM-10 by 85% and 115% at 0.3 and 3 μM, respectively. In HIPEC cells, venlafaxine at 0.03 and 0.3 μM, increased ADAM-10 mRNA levels by 156% and 167%, respectively.
This study shows that SSRIs may affect evTBs homeostasis at therapeutic levels and provides guidance for future research.
有 2%到 10%的孕妇会因抑郁症而接受选择性 5-羟色胺再摄取抑制剂（SSRIs）治疗。滋养细胞外胚层（evTBs）迁移并侵入母体组织，对于胚胎着床和母体螺旋动脉重塑至关重要。evTBs 迁移和侵入不良可能导致严重的妊娠并发症，但 SSRIs 对这些过程的影响从未被研究过。为了确定五种 SSRIs（氟西汀、去甲氟西汀、西酞普兰、舍曲林和文拉法辛）对迁移/侵袭的影响，我们使用 JEG-3 和 HIPEC 细胞作为 evTB 模型。
用递增浓度（0.03-10 μM）的 SSRIs 处理细胞。使用基于阻抗的系统监测细胞增殖，用流式细胞术监测细胞周期。通过划痕试验确定迁移，通过酶谱法确定金属蛋白酶（MMP）活性。通过 RT-qPCR 确定侵袭标志物。
氟西汀和舍曲林（10 μM）分别使 JEG-3 细胞的细胞增殖减少 94%和 100%，使 HIPEC 细胞的细胞增殖减少 58.6%和 100%。去甲氟西汀在 0.03 μM 时使 JEG-3 细胞的 MMP-9 活性增加 2.0%，在 3 μM 时增加 43.9%，但在 3 μM 时使 HIPEC 细胞的 MMP-9 活性减少 63.7%。舍曲林在 0.03 μM 时使 JEG-3 细胞的 TIMP-1 mRNA 水平增加 36%，在 0.3 和 3 μM 时分别增加 85%和 115%，ADAM-10 mRNA 水平分别增加 85%和 115%。在 HIPEC 细胞中，文拉法辛在 0.03 和 0.3 μM 时，ADAM-10 mRNA 水平分别增加 156%和 167%。
本研究表明，SSRIs 可能会在治疗水平上影响 evTBs 的稳态，并为未来的研究提供指导。
