Abstract P268: Overexpression of miR-210 Induces Preeclampsia-like Symptoms in Pregnant Mice by Attenuating the STAT6/IL-4 Pathway

Abstract

Preeclampsia (PE) is a pregnancy-related hypertensive disorder that affects 5-8% of all pregnancies worldwide. Placental microRNA (miRNA) expression is known to be dysregulated during PE which includes miR-210. However, the role of miR-210 in the development of PE is still unknown. We have previously demonstrated STAT6, a transcription factor, to be a direct target of miR-210. In addition, STAT6 modulates levels of IL-4, an anti-inflammatory cytokine which is known to be beneficial during pregnancy. Given that the STAT6/IL-4 pathway is important for normal pregnancy, we hypothesized that an overexpression of miR-210 in mice will contribute to PE-like symptoms by inhibiting the STAT6/IL-4 pathway. Systolic blood pressures (SBP) were measured using the tail-cuff method on both WT (C57Bl/6J) and miR-210 TG mice. The miR-210 TG mice exhibited increased SBP compared to the WT mice (WT: 95±2 mmHg, miR-210 TG: 115±2.4 mmHg, p<0.05). The miR-210 TG mice also displayed endothelial dysfunction measured by aortic vascular reactivity using wire myography (WT: 93% miR-210 TG: 68% relaxation, p<0.05 vs. WT) and a significant increase in proteinuria (4 fold, p<0.05 vs. WT). Furthermore, the miR-210 TG mice exhibit placental necrosis and a significant increase in the number of malformed pups. Placental STAT6 levels decreased in miR-210 TG compared to WT mice (2.6 fold, p<0.05 vs. WT) as determined by immunoblotting. In addition, qRT-PCR analysis of the miR-210 TG placentas exhibited a (4.8 fold, p<0.05 vs. WT) decrease in IL-4 expression. Immunoblotting and immunohistochemistry (IHC) studies showed a decrease in IL-4 levels (2.4 fold, p<0.05 vs. WT) and immunoreactivity in the miR-210 TG placentas as well as. IHC studies in human placentas also showed a decrease in both IL-4 and STAT6. Based on our results, miR-210 overexpression induces PE-like symptoms including hypertension, endothelial dysfunction, proteinuria, and malformed pups in pregnant mice. In addition, miR-210 overexpression attenuated the STAT6/IL-4 anti-inflammatory pathway. Our data suggests that either targeting miR-210 or the STAT6/1L-4 pathway could be a potential therapeutic in mitigating the symptoms of PE.