早发性先兆子痫（EOPE）是一种严重的妊娠并发症，与着床时滋养层分化和功能缺陷有关，但其表型在妊娠晚期表现出来。目前尚无可靠的方法来早期预测和治疗 EOPE。肾上腺髓质素（ADM）是妊娠早期丰富的胎盘肽。综合单细胞测序和空间转录组学证实 ADM 在人绒毛细胞滋养层和合体滋养层中高表达。后来发生 EOPE 的妊娠早期孕妇的绒毛膜绒毛和血清中 ADM 水平低于血压正常妊娠的孕妇。 ADM 在体外刺激滋养层干细胞和滋养层类器官的分化。在怀孕小鼠中，胎盘特异性 ADM 抑制导致了 EOPE 样表型。小鼠 PE 模型中的 EOPE 样表型通过基于胎盘特异性纳米颗粒的 ADM 强制表达而减少。我们的研究揭示了滋养层 ADM 在胎盘发育、EOPE 发病机制中的作用及其潜在的临床用途。

Early-onset preeclampsia (EOPE) is a severe pregnancy complication associated with defective trophoblast differentiation and functions at implantation, but manifestation of its phenotypes is in late pregnancy. There is no reliable method for early prediction and treatment of EOPE. Adrenomedullin (ADM) is an abundant placental peptide in early pregnancy. Integrated single-cell sequencing and spatial transcriptomics confirm a high ADM expression in the human villous cytotrophoblast and syncytiotrophoblast. The levels of ADM in chorionic villi and serum were lower in first-trimester pregnant women who later developed EOPE than those with normotensive pregnancy. ADM stimulates differentiation of trophoblast stem cells and trophoblast organoids in vitro. In pregnant mice, placenta-specific ADM suppression led to EOPE-like phenotypes. The EOPE-like phenotypes in a mouse PE model were reduced by a placenta-specific nanoparticle-based forced expression of ADM. Our study reveals the roles of trophoblastic ADM in placental development, EOPE pathogenesis, and its potential clinical uses.