Abstract 038: MiR-210 Overexpression Induces sFlt1 Production and Contributes to Preeclampsia-like Symptoms in Pregnant Mice

Abstract

Preeclampsia (PE) is an obstetric complication that is diagnosed by hypertension and proteinuria at or after 20 weeks of gestation. PE is a multifactorial disease, but it is widely accepted that impaired proangiogenic factors such as vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and antiangiogenic factor such as soluble FMS-like tyrosine kinase-1 (sFlt1) or VEGF receptor-1 balance during pregnancy is linked to PE. sFlt1, a splice variant of Flt1 binds to either VEGF or PlGF and blocks their action. In addition, placental angiogenesis is known to be regulated by specific miRNAs that are typically dysregulated during PE highlighting the importance of these miRNAs in pregnancy disorders. miR-210 is upregulated in placentas and serum/plasma of PE women and is also known to modulate angiogenic pathways. Therefore, we hypothesized that miR-210 overexpression contributes to the development of PE-like symptoms by altering the angiogenic/antiangiogenic pathway. To this end, we demonstrate increased systolic blood pressure (SBP: miR-210 TG P = 115 ± 2 mm Hg vs. WT P = 95 ± 2 mm Hg, p<0.05), endothelial dysfunction and proteinuria in pregnant miR-210 TG mice as compared to control WT mice. Placental sFlt-1 levels increased and PlGF levels decreased in miR-210 TG mice as determined by immunoblotting. Immunohistochemistry (IHC) analysis demonstrated an increase in sFlt1 and a decrease in PlGF immunoreactivity in miR-210 TG placentas. Pregnant miR-210 TG mice exhibited increased serum levels of sFlt-1 as well as decreased PlGF as compared to pregnant WT mice. Furthermore, immunohistological analysis of stained human placental sections revealed an increase in sFlt-1 and a decrease in PlGF in pregnant miR-210 TG as compared to pregnant WT mice. To determine the placental etiology, human cytotrophoblasts (CTBs) overexpressing miR-210 demonstrated a decrease in PlGF while inhibition of miR-210 in CTBs using anti-miR-210 oligos increased the PlGF expression as determined by immunoblotting. These data taken together suggest that miR-210 modulates the angiogenic/antiangiogenic pathway and contributes to PE-like features in mice. Thus, targeting miR-210 by delivering anti-miR-210 oligos may prevent PE-like symptoms in pregnant women.