MicroRNA‐29 differentially mediates preeclampsia‐dysregulated cellular responses to cytokines in female and male fetal endothelial cells

Abstract

Preeclampsia (PE) differentially impairs female and male fetal endothelial cell function, which is associated with an increased risk of adult‐onset cardiovascular disorders in children born to mothers with PE. However, the underlying mechanisms are poorly defined. We hypothesize that dysregulation of microRNA‐29a‐3p and 29c‐3p (miR‐29a/c‐3p) in PE disturbs gene expression and cellular responses to cytokines in fetal endothelial cells in a fetal sex‐dependent manner. RT‐qPCR analysis of miR‐29a/c‐3p was performed on female and male unpassaged (P0) human umbilical vein endothelial cells (HUVECs) from normotensive (NT) pregnancies and PE. Bioinformatic analysis of an RNA‐seq dataset was performed to identify PE‐dysregulated miR‐29a/c‐3p target genes in female and male P0‐HUVECs. Gain‐ and loss‐of‐function assays were conducted to determine the effects of miR‐29a/c‐3p on endothelial monolayer integrity and proliferation in response to transforming growth factor‐β1 (TGFβ1) and tumour necrosis factor‐α (TNFα) in NT and PE HUVECs at passage 1. We observed that PE downregulated miR‐29a/c‐3p in male and female P0‐HUVECs. PE dysregulated significantly more miR‐29a/c‐3p target genes in female vs. male P0‐HUVECs. Many of these PE‐differentially dysregulated miR‐29a/c‐3p target genes are associated with critical cardiovascular diseases and endothelial function. We further demonstrated that miR‐29a/c‐3p knockdown specifically recovered the PE‐abolished TGFβ1‐induced strengthening of endothelial monolayer integrity in female HUVECs, while miR‐29a/c‐3p overexpression specifically enhanced the TNFα‐promoted cell proliferation in male PE HUVECs. In conclusion, PE downregulates miR‐29a/c‐3p expression and differentially dysregulates miR‐29a/c‐3p target genes associated with cardiovascular diseases and endothelial function in female and male fetal endothelial cells, possibly contributing to the fetal sex‐specific endothelial dysfunction observed in PE. imageKey points Preeclampsia differentially impairs female and male fetal endothelial cell function in responses to cytokines. Pro‐inflammatory cytokines are elevated in maternal circulation during pregnancy in preeclampsia. MicroRNAs are critical regulators of endothelial cell function during pregnancy. We have previously reported that preeclampsia downregulated microRNA‐29a‐3p and 29c‐3p (miR‐29a/c‐3p) in primary fetal endothelial cells. However, it is unknown if PE differentially dysregulates the expression of miR‐29a/c‐3p in female and male fetal endothelial cells. We show that preeclampsia downregulates miR‐29a/c‐3p in male and female HUVECs and preeclampsia dysregulates cardiovascular disease‐ and endothelial function‐associated miR‐29a/c‐3p target genes in HUVECs in a fetal sex‐specific manner. MiR‐29a/c‐3p differentially mediate cell responses to cytokines in female and male fetal endothelial cells from preeclampsia. We have revealed fetal sex‐specific dysregulation of miR‐29a/c‐3p target genes in fetal endothelial cells from preeclampsia. This differential dysregulation may contribute to fetal sex‐specific endothelial dysfunction in offspring born to preeclamptic mothers.

An Endogenous Aryl Hydrocarbon Receptor Ligand Induces Preeclampsia-like Phenotypes: Transcriptome, Phosphoproteome, and Cell Functions

“…Additionally, human umbilical vein endothelial cells (HUVECs) from PE exhibit increased cell permeability 5 and reduced nitric oxide (NO) production 6 . We have also reported that PE dysregulates transcriptome and angiogenic responses in HUVECs in a fetal sex-specific manner 7,8 , supporting the importance of sexually dimorphic regulation of endothelial functions in PE. Currently, the etiology of PE is known although many factors may contribute to the development of PE 2 .…”

Identification and Analysis of Sex-Biased MicroRNAs in Human Diseases

“…Kahnamoui et al found that respiratory sensitivity was associated with miRNA expression levels in mice of different sexes [ 8 ]; Rosenberg et al found an association between the effects of different sexes on smoking and lung development [ 9 ]. In addition, research showed that certain miRNAs are expressed differently in different sexes during fetal development [ 10 , 11 ], which, in turn, results in different developmental processes. There have even been studies of male–female gender differences in miRNA-associated methylation modifications during solid tumor pathology [ 12 ].…”