Downregulation of CMIP contributes to preeclampsia development by impairing trophoblast function via the PDE7B-cAMP pathway.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.