Sex-Specific Disruption in Human Placental miRNAs and mRNAs Involved in IUGR Placental Insufficiency and Capillary Angiogenesis

Abstract

Intrauterine growth restriction (IUGR) is one of the most common pregnancy complications culminating in adverse fetal outcome, including preterm birth, neonatal mortality and stillbirth. Compromised placental development and function, especially disruption in angiogenesis and inadequate nutrient supply are contributing factors. Fetal sex also influences placental function. Knowledge of gene expression changes and epigenetic factors contributing to placental dysfunction in IUGR pregnancies will help identify biomarkers and help target interventions. This study tested the hypothesis that IUGR pregnancies are associated with sexually-dimorphic disruptions in miRNA - an epigenetic factor and mRNAs invloving key mediators of angiogenesis and microvessel development. Changes in expression of key genes/proteins involved in placental dysfunction by RT-PCR and immunohistochemistry and miRNA changes by RNA sequencing were undertaken with term placenta from 12 control and 20 IUGR pregnancies. Findings showed sex-dependent changes in expression of genes involved in steroidogenesis, steroid action, IGF family members, inflammatory cytokines and angiogenic factors in IUGR pregnancies. In addition, upregulation of MIR451A and downregulation of MIR543 in placentas from IUGR group with female newborns and upregulation of MIR520G in placentas from IUGR group with male newborns were also noted. MIR451A and MIR543 have been implicated in angiogenesis. Consistent with gene changes, CD34, the microvessel angiogenesis marker, also showed reduced staining only in female IUGR group. These findings provide evidence in support of sexual dimorphism in the capillary development of IUGR manifested at the level of key mediators of placental angiogenesis and placental function that include changes in expression of miRNA with potential to serve as biomarkers.