INRS-Institut Armand-Frappier, Université du Québec, Laval, QC H7V 1B7, Canada.
Placenta. 2010 May;31(5):439-47. doi: 10.1016/j.placenta.2010.02.019. Epub 2010 Mar 25.
Previous results from our group have demonstrated the expression of the 5-HT(2A) receptor and a mitogenic effect of serotonin in human trophoblast. The objectives of the present study were to investigate the role of the 5-HT(2A) receptor in trophoblast cells and to determine the signalling pathways activated by this receptor. We investigated the effect of (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), a selective 5-HT(2A) agonist, on cell cycle progression and cell viability in BeWo and JEG-3 cells. We also investigated, by co-immunoprecipitation and western blot analysis, the involvement of the MEK-ERK1/2 and JAK2-STAT3 signalling pathways following activation of the placental 5-HT(2A) receptor. Our results showed a concentration-dependent increase of cell viability by DOI, which was reversed by ketanserin, a selective 5-HT(2A) receptor antagonist. Furthermore, activation of the 5-HT(2A) receptor by DOI increased cell entry into the G2/M and S phase (DNA synthesis) in BeWo and JEG-3 cells, respectively. In addition, stimulation of BeWo and JEG-3 cells by DOI activated both the MEK-ERK1/2 and the JAK2-STAT3 signalling pathways. This study demonstrated that the 5-HT(2A) receptor increases cell viability and affects cell cycle progression in human trophoblast cell lines as well as activates the MEK-ERK1/2 and JAK2-STAT3 intracellular signalling pathways, which are related to survival, differentiation, migration and invasion. These findings indicate that serotonin through the activation of the 5-HT(2A) receptor is a key regulator of placentation and may play a role in the pathophysiology of certain pregnancy disorders associated with alterations in placental development, such as preeclampsia, gestational diabetes and preterm birth.
先前我们的研究小组已经证明了 5-羟色胺（2A）受体在人滋养层中的表达及其对丝氨酸的有丝分裂作用。本研究的目的是研究 5-羟色胺（2A）受体在滋养层细胞中的作用，并确定该受体激活的信号通路。我们研究了 (+/-)-2,5-二甲氧基-4-碘苯丙胺盐酸盐（DOI），一种选择性 5-羟色胺（2A）激动剂，对 BeWo 和 JEG-3 细胞周期进程和细胞活力的影响。我们还通过共免疫沉淀和 Western blot 分析研究了胎盘 5-羟色胺（2A）受体激活后 MEK-ERK1/2 和 JAK2-STAT3 信号通路的参与。我们的结果表明，DOI 浓度依赖性地增加细胞活力，这种作用可被选择性 5-羟色胺（2A）受体拮抗剂酮色林所逆转。此外，DOI 激活 5-羟色胺（2A）受体可分别增加 BeWo 和 JEG-3 细胞进入 G2/M 和 S 期（DNA 合成）。此外，DOI 刺激 BeWo 和 JEG-3 细胞激活了 MEK-ERK1/2 和 JAK2-STAT3 信号通路。本研究表明，5-羟色胺（2A）受体通过增加细胞活力并影响人滋养层细胞系的细胞周期进程，以及激活 MEK-ERK1/2 和 JAK2-STAT3 细胞内信号通路，与生存、分化、迁移和侵袭有关。这些发现表明，通过激活 5-羟色胺（2A）受体，血清素是胎盘形成的关键调节剂，可能在与胎盘发育改变相关的某些妊娠疾病的病理生理学中发挥作用，例如子痫前期、妊娠期糖尿病和早产。
