Abstract
An imbalance in angiogenic growth factors and poor utero-placental perfusion are strongly associated with preeclampsia. The reduced utero-placental perfusion (RUPP) model that mimics insufficient placental perfusion is used to study preeclampsia. The aim of this study was to develop a refined RUPP model in C57Bl/6 J mice to test the efficacy of MZe786 as a potential inhibitor of soluble Flt-1 for preeclampsia therapy. Murine RUPP (mRUPP) was induced through bilateral ligation of the ovarian arteries at E11.5 that resulted in typical preeclampsia symptoms including increase in mean arterial pressure (MAP), kidney injury and elevated soluble Flt-1 (sFlt-1) levels in the maternal plasma and amniotic fluid. The murine RUPP kidneys showed tubular and glomerular damage along with increased oxidative stress characterised by increased nitrotyrosine staining. The mRUPP displayed abnormal placental vascular histology, reduced expression of placental cystathionine γ-lyase (CSE), the hydrogen sulfide (H2S) producing enzyme, and resulted in adverse fetal outcomes (FGR). Importantly, oral administration of hydrogen sulfide (H2S)-releasing compound MZe786 from E11.5 to E17.5 successfully prevented the development of preeclampsia. Specifically, MZe786 treatment reduced maternal MAP and kidney nitrotyrosine staining and improved fetal outcome. The circulation levels of sFlt-1 were dramatically decreased in MZe786 treated animals implying that H2S released from MZe786 offered protection by inhibiting sFlt-1 levels. MZe786 prevent preeclampsia and warrant a rapid move to randomised control clinical trial.
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•Refined mouse reduced uterine perfusion pressure (mRUPP) model exhibits preeclampsia symptoms.•Mouse RUPP induces maternal hypertension, kidney injury, elevates circulating sFlt-1 levels and promotes nitrosative stress.•Mouse RUPP reduces expression of the protective enzyme, placental cystathionine γ-lyase and causes poor fetal outcome.•H2S releasing aspirin, MZe786, acts as an inhibitor of sFlt-1 to successfully prevent preeclampsia and improve fetal outcome.•MZe786 is a novel drug with therapeutic potential to prevent preeclampsia.