MicroRNAs Target Decidual Angiogenic Factors During Early Pregnancy in BPH/5, a Spontaneous Mouse Model of Preeclampsia

Preeclampsia (PE) is a hypertensive disease that affects up to 10% of pregnant women worldwide. It presents as late gestational hypertension/proteinuria and only resolves upon delivery of the fetus and placenta. Despite being a leading cause of maternal and fetal morbidity/mortality, the underlying mechanism(s) is unknown. Previous research indicates that abnormal placental development plays a key role in PE. Proper placental formation is dependent on successful implantation and decidualization, the essential process of uterine angiogenesis prior to trophoblast invasion and placentation. Using the BPH/5 spontaneous genetic mouse model of PE, we have previously described profound periimplantation defects in early pregnancy with the principle dysregulated factor being cyclooxygenase 2 (Cox2). Preliminary data indicates that uterine Cox2 misexpression plays a causal role in PE. As Cox2 is heavily regulated by micro(mi)RNAs during the periimplantation period in mice, we hypothesized that miRNAs play a key role in the periimplantation defects seen in the preeclamptic BPH/5 mouse. To test this hypothesis, miRNA sequencing was performed on BPH/5 and C57 control implantation sites collected at e7.5 of pregnancy, the day of peak decidualization. Twenty‐one differentially expressed miRNAs were identified (≥1.5‐fold difference, p < 0.05) with the top 9 being downregulated in BPH/5 implantation sites. Bioinformatic analyses identified potential targets related to angiogenesis. Interestingly, one of these was miR‐146a (−2.2‐fold vs C57), which targets vascular endothelial growth factor (VEGF)‐A. Vegf mRNA levels in e7.5 BPH/5 implantation sites are comparable to C57 as measured by qRT‐PCR, however VEGF 164 protein is significantly upregulated in BPH/5 e7.5 implantation sites (1.013 ± 0.25 vs C57: 0.1580 ± 0.1, n =7, p<0.05). Further studies are warranted to confirm if miR‐146a is playing a causal role in the VEGF 164 expression pattern. PE is characterized by an imbalance in placental angiogenic factors; however, regulation of these factors during decidualization in the context of PE is unknown. This will provide better understanding of the relationship of miRNAs and angiogenic factors in the decidua before placenta formation and the onset of the maternal syndrome in BPH/5 mice. These findings may provide insights into the origins of the angiogenic imbalance observed in PE pregnancies. Support or Funding Information Studies described herein were supported in part by a seed grant from the Cornell Center for Reproductive Genomics, using funds obtained as part of the NICHD National Centers for Translational Research in Reproduction and Infertility (NCTRI), award number P50HD076210 (PI: P.E. Cohen).