Hung Tai-Ho, Wu Chung-Pu, Chen Szu-Fu
Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei, Taiwan.
Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.
Front Med (Lausanne). 2021 Dec 6;8:788969. doi: 10.3389/fmed.2021.788969. eCollection 2021.
Dysregulation of placental mechanistic target of rapamycin (mTOR) activity has been implicated in the pathophysiology of pregnancies complicated by idiopathic fetal growth restriction (FGR) and gestational diabetes mellitus (GDM) with large-for-gestational-age (LGA) infants. However, the underlying mechanisms remain unclear. We obtained placentas from women with normal pregnancies ( = 11) and pregnancies complicated by FGR ( = 12) or GDM with LGA infants ( = 12) to compare the levels of total and phosphorylated forms of Akt, AMPK, TSC2, and mTOR among the three groups and used primary cytotrophoblast cells isolated from 30 normal term placentas to study the effects of oxygen-glucose deprivation (OGD) and increasing glucose concentrations on the changes of these factors . Placentas from FGR pregnancies had lower phosphorylated Akt (p-Akt) levels ( < 0.05), higher p-AMPKα levels ( < 0.01), and lower mTOR phosphorylation ( < 0.05) compared to that of normal pregnant women. Conversely, women with GDM and LGA infants had higher p-Akt ( < 0.001), lower p-AMPKα ( < 0.05), and higher p-mTOR levels ( < 0.05) in the placentas than normal pregnant women. Furthermore, primary cytotrophoblast cells subjected to OGD had lower p-Akt and p-mTOR (both < 0.05) and higher p-AMPKα levels ( < 0.05) than those cultured under standard conditions, but increasing glucose concentrations had opposite effects on the respective levels. Administering compound C, an AMPK inhibitor, did not significantly affect Akt phosphorylation but partially reversed mTOR phosphorylation. Administering LY294002, an Akt inhibitor, decreased p-mTOR levels, but did not change the levels of total and phosphorylated AMPKα. These results suggest that Akt and AMPK are involved in the regulation of trophoblast mTOR activity in the placentas of pregnancies complicated by FGR and GDM with LGA infants.
胎盘雷帕霉素机制性靶标（mTOR）活性失调与并发特发性胎儿生长受限（FGR）以及伴有大于胎龄儿（LGA）的妊娠期糖尿病（GDM）的妊娠病理生理学有关。然而，其潜在机制仍不清楚。我们获取了正常妊娠女性（n = 11）以及并发FGR（n = 12）或伴有LGA婴儿的GDM（n = 12）女性的胎盘，以比较三组中Akt、AMPK、TSC2和mTOR的总形式和磷酸化形式的水平，并使用从30个足月正常胎盘分离的原代细胞滋养层细胞来研究氧葡萄糖剥夺（OGD）和葡萄糖浓度升高对这些因子变化的影响。与正常妊娠女性相比，FGR妊娠胎盘的磷酸化Akt（p-Akt）水平较低（P < 0.05），p-AMPKα水平较高（P < 0.01），mTOR磷酸化水平较低（P < 0.05）。相反，患有GDM和LGA婴儿的女性胎盘的p-Akt水平较高（P < 0.001），p-AMPKα水平较低（P < 0.05），p-mTOR水平较高（P < 0.05）。此外，与在标准条件下培养的细胞相比，经历OGD的原代细胞滋养层细胞的p-Akt和p-mTOR水平较低（均为P < 0.05），p-AMPKα水平较高（P < 0.05），但葡萄糖浓度升高对各自水平有相反的影响。给予AMPK抑制剂化合物C对Akt磷酸化没有显著影响，但部分逆转了mTOR磷酸化。给予Akt抑制剂LY294002降低了p-mTOR水平，但没有改变总AMPKα和磷酸化AMPKα的水平。这些结果表明，Akt和AMPK参与了并发FGR以及伴有LGA婴儿的GDM的妊娠胎盘中滋养层mTOR活性的调节。
