FGR-associated placental insufficiency and capillary angiogenesis involves disruptions in human placental miRNAs and mRNAs

Wenhui Song; Qing Guo; Muraly Puttabyatappa; Venkateswaran Ramamoorthi Elangovan; Jianping Wang; Fang Li; Fangfang Liu; Xuejie Bi; Haiying Li; Guangping Fu; Vasantha Padmanabhan; XiaoHua Wu

doi:10.1016/j.heliyon.2024.e28007

FGR-associated placental insufficiency and capillary angiogenesis involves disruptions in human placental miRNAs and mRNAs

Heliyon. 2024 Mar 13;10(6):e28007. doi: 10.1016/j.heliyon.2024.e28007. eCollection 2024 Mar 30.

Authors

Wenhui Song^{1

2}, Qing Guo^{1

2

3}, Muraly Puttabyatappa⁴, Venkateswaran Ramamoorthi Elangovan⁴, Jianping Wang², Fang Li², Fangfang Liu², Xuejie Bi², Haiying Li², Guangping Fu⁵, Vasantha Padmanabhan⁴, XiaoHua Wu^{1

2}

Affiliations

¹ Department of Obstetrics and Gynecology, Hebei Medical University, Shijiazhuang, Hebei, PR China.
² The Fourth Hospital of Shijiazhuang affiliated to Hebei Medical University, Shijiazhuang, Hebei, PR China.
³ Department of Obstetrics and Gynecology, Hebei Key Laboratory of Maternal and Fetal Medicine, Shijiazhuang, Hebei, PR China.
⁴ Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
⁵ Hebei Key Laboratory of Forensic Medicine, College for Forensic Medicine, Hebei Medical University, Shijiazhuang, Hebei, PR China.

Abstract

Fetal growth restriction (FGR) 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 FGR pregnancies will help identify biomarkers and help target interventions. This study tested the hypothesis that FGR pregnancies are associated with disruptions in miRNA - an epigenetic factor and mRNAs involving 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 FGR pregnancies. Findings showed changes in expression of genes involved in steroidogenesis, steroid action, IGF family members, inflammatory cytokines and angiogenic factors in FGR pregnancies. In addition, upregulation of MIR451A and downregulation of MIR543 in placentas from FGR group with female newborns and upregulation of MIR520G in placentas from FGR 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 FGR group. These findings provide evidence that epigentically regulated gene expression changes in angiogenesis and capillary development influence placental impairment in FGR pregnancies. Our preliminary observations also support for these changes to be driven in a sex-specific manner.

Keywords: Angiogenesis; Epigenetics; FGR; Inflammation; Placenta; miRNA.