State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Ministry of Education-International Collaborative Laboratory of Reproduction and Development, Chongqing Medical University, Chongqing, China.
Cell Prolif. 2023 Feb;56(2):e13358. doi: 10.1111/cpr.13358. Epub 2022 Dec 8.
Pre-eclampsia (PE) is deemed an ischemia-induced metabolic disorder of the placenta due to defective invasion of trophoblasts during placentation; thus, the driving role of metabolism in PE pathogenesis is largely ignored. Since trophoblasts undergo substantial glycolysis, this study aimed to investigate its function and regulatory mechanism by AMPK in PE development. Metabolomics analysis of PE placentas was performed by gas chromatography-mass spectrometry (GC-MS). Trophoblast-specific AMPKα1-deficient mouse placentas were generated to assess morphology. A mouse PE model was established by Reduced Uterine Perfusion Pressure, and placental AMPK was modulated by nanoparticle-delivered A769662. Trophoblast glucose uptake was measured by 2-NBDG and 2-deoxy-d-[ H] glucose uptake assays. Cellular metabolism was investigated by the Seahorse assay and GC-MS.PE complicated trophoblasts are associated with AMPK hyperactivation due not to energy deficiency. Thereafter, AMPK activation during placentation exacerbated PE manifestations but alleviated cell death in the placenta. AMPK activation in trophoblasts contributed to GLUT3 translocation and subsequent glucose metabolism, which were redirected into gluconeogenesis, resulting in deposition of glycogen and accumulation of phosphoenolpyruvate; the latter enhanced viability but compromised trophoblast invasion. However, ablation of AMPK in the mouse placenta resulted in decreased glycogen deposition and structural malformation. These data reveal a novel homeostasis between invasiveness and viability in trophoblasts, which is mechanistically relevant for switching between the 'go' and 'grow' cellular programs.
子痫前期（PE）被认为是胎盘滋养细胞侵袭缺陷导致的胎盘缺血性代谢紊乱；因此，代谢在 PE 发病机制中的驱动作用在很大程度上被忽视了。由于滋养细胞经历大量的糖酵解，本研究旨在通过 AMPK 研究其在 PE 发展中的功能和调节机制。通过气相色谱-质谱联用（GC-MS）对 PE 胎盘进行代谢组学分析。生成滋养细胞特异性 AMPKα1 缺陷型小鼠胎盘以评估形态。通过减少子宫灌注压建立小鼠 PE 模型，并通过纳米颗粒递送 A769662 调节胎盘 AMPK。通过 2-NBDG 和 2-脱氧-d-[H]葡萄糖摄取测定法测量滋养细胞葡萄糖摄取。通过 Seahorse 测定法和 GC-MS 研究细胞代谢。PE 复杂的滋养细胞与 AMPK 过度激活有关，而不是能量缺乏。此后，在胎盘形成过程中 AMPK 的激活加剧了 PE 的表现，但减轻了胎盘细胞死亡。滋养细胞中 AMPK 的激活导致 GLUT3 易位和随后的葡萄糖代谢，这些代谢被重新定向为糖异生，导致糖原沉积和磷酸烯醇丙酮酸的积累；后者增强了活力，但损害了滋养细胞的侵袭。然而，在小鼠胎盘中敲除 AMPK 会导致糖原沉积减少和结构畸形。这些数据揭示了滋养细胞中侵袭性和活力之间的一种新的平衡，这在从“生长”到“生长”的细胞程序转换中具有机械相关性。
