Li Yina, Yan Xinjing, Yu Haiyang, Zhou Yuanbo, Gao Yongrui, Zhou Xinyuan, Yuan Yujie, Ding Yangnan, Shi Qianqian, Fang Yang, Du Hongmei, Yuan Enwu, Zhao Xin, Zhang Linlin
Department of Laboratory Medicine, Third Affiliated Hospital of Zhengzhou University, 7 Kangfu Qian Street, Zhengzhou, Henan, 450052, People's Republic of China.
Zhengzhou Key Laboratory for In Vitro Diagnosis of Hypertensive Disorders of Pregnancy, Zhengzhou, China.
Cell Mol Life Sci. 2025 May 15;82(1):203. doi: 10.1007/s00018-025-05726-5.
Preeclampsia (PE) is one of the leading causes of perinatal maternal and fetal morbidity and mortality, but its precise mechanism remains elusive. Previous research has suggested that c-Maf-inducible protein (CMIP) is abnormally expressed in PE pathophysiology. Therefore, we aimed to explore the potential role of CMIP and its downstream molecules in PE.
Multiplex immunofluorescence and immunohistochemical assays were conducted on preeclamptic placentas. Functional analysis of CMIP was performed in HTR-8/SVneo cells through transfection experiments in which either CMIP was overexpressed or downregulated. RNA sequencing was utilized to identify the molecular pathways downstream of CMIP. The impact of hypoxia on CMIP levels was assessed in three different types of trophoblast cells. The therapeutic efficacy of CMIP was evaluated in an N(ω)-nitro-L-arginine methyl ester (L-NAME)-induced rat model of PE.
CMIP expression was downregulated in extrachorionic trophoblasts (EVTs) and syncytiotrophoblasts (STBs) in preeclamptic placentas. This downregulation of CMIP in trophoblast cells disrupts cell proliferation, migration, invasion, and angiogenesis by upregulating the PDE7B-cAMP pathway, while elevated CMIP levels enhance these cellular functions. Hypoxia reduced CMIP expression in all three types of trophoblast cells. Moreover, in a rat model of PE, supplementation with CMIP alleviated hypertension and increased fetal weight and number.
Our study demonstrates for the first time that the CMIP-PDE7B-cAMP pathway contributes to PE development by influencing trophoblast function. The signaling pathway proteins involved in PE induced by CMIP may provide new clues to the occurrence of PE and new targets for future PE therapy.
子痫前期（PE）是围产期孕产妇和胎儿发病及死亡的主要原因之一，但其确切机制仍不清楚。先前的研究表明，c-Maf诱导蛋白（CMIP）在PE病理生理学中表达异常。因此，我们旨在探讨CMIP及其下游分子在PE中的潜在作用。
对子痫前期胎盘进行多重免疫荧光和免疫组织化学检测。通过转染实验在HTR-8/SVneo细胞中对CMIP进行功能分析，其中CMIP要么过表达，要么下调。利用RNA测序来鉴定CMIP下游的分子途径。在三种不同类型的滋养层细胞中评估缺氧对CMIP水平的影响。在N（ω）-硝基-L-精氨酸甲酯（L-NAME）诱导的PE大鼠模型中评估CMIP的治疗效果。
子痫前期胎盘的绒毛外滋养层细胞（EVT）和合体滋养层细胞（STB）中CMIP表达下调。滋养层细胞中CMIP的这种下调通过上调PDE7B-cAMP途径破坏细胞增殖、迁移、侵袭和血管生成，而CMIP水平升高则增强这些细胞功能。缺氧降低了所有三种类型滋养层细胞中的CMIP表达。此外，在PE大鼠模型中，补充CMIP可缓解高血压，并增加胎儿体重和数量。
我们的研究首次证明CMIP-PDE7B-cAMP途径通过影响滋养层细胞功能促进PE的发展。CMIP诱导的PE中涉及的信号通路蛋白可能为PE的发生提供新线索，并为未来PE治疗提供新靶点。
