miRNA-543 attenuates placental angiogenesis in female fetal growth restriction by targeting ANGPT2 and inhibiting the PI3K/AKT/mTOR pathway.

Authors

Wenhui Song, Xuemei Yang, Chunyan Yang, Yuanyuan Zhao, Xinxian Zhang, Qing Guo

Published in

Frontiers in cell and developmental biology. Volume 14. Pages 1912518. Epub Oct 16, 2026.

Abstract

Insufficient placental angiogenesis is a predominant pathological cause of fetal growth restriction (FGR). Placental capillary development is regulated in a sex-dependent manner, with female placentas exhibiting greater susceptibility to angiogenic dysfunction than male placentas. However, the sex-specific interplay between microRNAs (miRNAs) and human placental angiogenesis in FGR pathogenesis remains poorly defined. Emerging transcriptomic sequencing evidence has implicated miR-543 as a pivotal regulator of impaired angiogenesis in female FGR placentas. This study aimed to elucidate the sex-dependent mechanistic role of miR-543 in modulating placental angiogenesis in a cell-specific manner.
FGR pregnancies were recruited, and placental tissues were collected after delivery. The dual-luciferase reporter assay was used to detect the direct binding site of miR-543 to ANGPT2. Next, immunohistochemistry (IHC) and immunofluorescence (IF) staining were used to detect the expression and localization of ANGPT2. To verify the cell-specific gene expression of miR-543 and ANGPT2, laser capture microdissection (LCM) was employed to isolate endothelial cells from human placentas. The gene expression levels of miR-543 and ANGPT2 were quantified by qRT-PCR. CCK8, wound healing, Transwell, and tube formation assays and flow cytometry were performed to assess the functional effects of miR-543 and ANGPT2 on the biological function of human umbilical vein endothelial cells (HUVECs). The PI3K/AKT/mTOR signaling pathway was predicted and verified by Western blotting.
Significantly downregulated miR-543 expression was observed in the placentas of female FGR fetuses relative to matched normal controls. According to target gene prediction and the dual-luciferase reporter assay, ANGTP2 was identified as a target candidate of miR-543. Moreover, immunofluorescence staining and LCM analysis verified the cell-specific distribution of ANGPT2 in female FGR placentas, partly indicating its key involvement in placental capillary angiogenesis. Furthermore, dysregulated expression of miR-543 and ANGPT2 was closely correlated with aberrant proliferation, migration, and apoptosis of HUVECs. KEGG analysis revealed that the candidate targets of miR-543 were mainly enriched in the PI3K/AKT/mTOR pathway. Western blot analysis demonstrated that the PI3K/AKT/mTOR signaling pathway mediated the ANGPT2-induced attenuation of placental angiogenesis in female FGR.
miR-543 negatively regulated ANGPT2 expression, leading to impaired endothelial cell function via inactivation of the PI3K/AKT/mTOR signaling pathway. This, in turn, contributed to sex-specific inhibition of capillary angiogenesis in the placenta of female fetuses. These findings reveal a novel miRNA-mediated, sex-dependent regulatory mechanism underlying the pathogenesis of impaired placental angiogenesis.

PMID:
42964304
Bibliographic data and abstract were imported from PubMed on 31 Oct 2026.

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