Elevated Hsa-miR-335-5p impairs trophoblast function and fetal growth in preeclampsia

Abstract

Background: Preeclampsia (PE) is a pregnancy complication associated with abnormal placental development and fetal growth restriction. Despite progress in understanding PE, the molecular mechanisms underlying its pathogenesis remain poorly defined. Exosomal miRNAs, particularly hsa-miR-335-5p, have been implicated in the regulation of placental function, but their exact role in PE requires further investigation.

Methods: We utilized advanced microfluidic chip technology to isolate and sequence serum exosomal miRNAs from PE patients and healthy controls. Functional assays were conducted to assess the effects of hsa-miR-335-5p overexpression on the proliferation, invasion, and apoptosis of trophoblast cells, especially under hypoxic conditions that replicate the placental microenvironment in PE. In vivo studies using a rat model were performed to examine the effects of elevated hsa-miR-335-5p on placental morphology and fetal growth. Mechanistic analysis was carried out to identify the target genes of hsa-miR-335-5p.

Results: Our analysis revealed a significant upregulation of hsa-miR-335-5p in the serum exosomes of PE patients compared to controls. Overexpression of hsa-miR-335-5p in trophoblast cells resulted in inhibited proliferation, decreased invasion, and increased apoptosis, particularly under hypoxic conditions. In vivo, rats with elevated hsa-miR-335-5p showed disrupted placental structure and fetal growth restriction. The mechanistic analysis identified MEF2D as a direct target of hsa-miR-335-5p, which plays a critical role in regulating trophoblast development and function.

Conclusion: This study establishes hsa-miR-335-5p as a key regulator in the pathogenesis of PE by targeting MEF2D and disrupting trophoblast function. These findings suggest that hsa-miR-335-5p could serve as a potential biomarker and therapeutic target for PE, offering new strategies for the diagnosis and treatment of this pregnancy complication.

Keywords: Exosomes; High-throughput sequencing; MEF2D; Microfluidic Chip; Preeclampsia; miRNA.