Zhou Chan, Zhu Yunqing, Zhang Liang, Zhao Miaomiao, Zhang Cong
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, China.
Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China.
Mol Ther Nucleic Acids. 2024 Nov 28;36(1):102408. doi: 10.1016/j.omtn.2024.102408. eCollection 2025 Mar 11.
Preeclampsia (PE) is a significant complication of pregnancy, occurring in approximately 10% of pregnancies. However, the underlying mechanisms of this condition remain unclear. Placentation and tumorigenesis both share many characteristics, but PE is the result of insufficient placentation, in contrast to the overaggression of tumorigenesis. AXL is a biomarker and therapeutic target for multiple metastatic cancers. We hypothesized that its downregulation could play a crucial role in the development of PE. In our study, we demonstrated that pregnan mice exhibited typical PE symptoms, such as hypertension, proteinuria, and inadequate trophoblast invasion and spiral artery remodeling. Cross-mating and embryo transplantation experiments confirmed that these phenotypes were caused by the decidua. RNA sequencing results revealed the abnormal expression of several transcripts in the decidua, including , which encodes a cardiac protease responsible for activating atrial natriuretic peptide (ANP). ANP is a cardiac hormone that regulates sodium homeostasis and blood pressure. Chromatin immunoprecipitation-qPCR analysis indicated that the decreased CORIN in decidua was due to reduced signal transducer and activator of transcription 3 (STAT3) binding. Treatment with ANP successfully alleviated the PE symptoms. Furthermore, we observed that in PE decidua, the level of AXL was significantly lower compared to normal pregnancies. These findings suggest that the dysregulation of decidua-derived AXL-CORIN-ANP signaling disrupts maternal-fetal crosstalk and contributes to the development of PE.
子痫前期（PE）是妊娠的一种重要并发症，约10%的妊娠会出现。然而，这种病症的潜在机制仍不清楚。胎盘形成和肿瘤发生有许多共同特征，但与肿瘤发生的过度侵袭相反，PE是胎盘形成不足的结果。AXL是多种转移性癌症的生物标志物和治疗靶点。我们假设其下调可能在PE的发生发展中起关键作用。在我们的研究中，我们证明孕鼠表现出典型的PE症状，如高血压、蛋白尿、滋养层细胞浸润不足和螺旋动脉重塑。杂交交配和胚胎移植实验证实这些表型是由蜕膜引起的。RNA测序结果揭示了蜕膜中几种转录本的异常表达，包括编码一种负责激活心房利钠肽（ANP）的心脏蛋白酶的转录本。ANP是一种调节钠稳态和血压的心脏激素。染色质免疫沉淀-qPCR分析表明，蜕膜中CORIN的减少是由于信号转导和转录激活因子3（STAT3）结合减少所致。用ANP治疗成功缓解了PE症状。此外，我们观察到，在PE蜕膜中，AXL水平明显低于正常妊娠。这些发现表明，蜕膜来源的AXL-CORIN-ANP信号失调会破坏母婴间的相互作用，并促进PE的发生发展。
