Luteolin decreases sFlt-1 and mean arterial pressure in the RUPP animal model of placental ischemia

Objectives: Preeclampsia (PE) is a complication of pregnancy and a leading cause of maternal and fetal morbidity and mortality. Despite being prevalent and highly morbid, there are no approved treatments to relieve PE signs and symptoms. Many studies have established that elevated levels of circulating anti-angiogenic soluble fms-like tyrosine kinase 1 (sFlt-1) protein drives the maternal syndrome observed in PE, and reductions in sFlt-1 improved symptoms. We have previously reported that the bioflavonoid luteolin reduces sFlt-1 expression and the vasoconstrictor endothelin-1 (ET-1) in vitro and dilates uterine arteries ex vivo. Here, we set out to determine whether luteolin reduces mean arterial pressure (MAP), sFlt-1, and ET-1, and improves uterine artery resistance index (UARI) in the reduced uterine perfusion pressure (RUPP) rat model of PE. Study design: On gestation day (GD) 14, animals were randomly separated into 4 groups: sham or RUPP treated with vehicle or luteolin (20 mg/kg/day). On GD19, MAP and UARI were measured, followed by blood and tissue collection. Main outcome measures: Placental protein expression of sFlt-1 and HIF-1α (Western blot) and circulating levels of sFlt-1, placental growth factor (PlGF) and ET-1 were measured (ELISA). Results: RUPP animals treated with luteolin demonstrated significant decreases in MAP, UARI, sFlt-1, and ET-1 compared to RUPP animals given a vehicle. There were no differences in sham animals treated with luteolin, and no adverse maternal or fetal outcomes were observed. Conclusions: Luteolin effectively reduced blood pressure, improved uterine artery flow impedance, and reduced antiangiogenic markers in the RUPP model of PE without any observable adverse effects.