Il-33 Supplementation Improves Vascular Function And Maternal Hypertension In Response To Placental Ischemia

Preeclampsia (PE), a leading cause of maternal and fetal morbidity and mortality, is a hypertensive pregnancy disorder with end-organ damage that develops after 20 weeks of gestation. PE is characterized by chronic immune activation, endothelial dysfunction, and fetal growth restriction (FGR). Clinical studies have shown decreased IL-33 signaling in PE women. We use the Reduced Uterine Perfusion Pressure (RUPP) rat model, which mimics many characteristics of PE patients including reduced IL-33 levels, to identify the mechanisms mediating maternal hypertension and FGR in PE. We hypothesized that IL-33 supplementation would improve maternal hypertension, fetal growth, and oxidative stress (ROS) during placental ischemia in pregnant rats. We implanted intraperitoneal mini-osmotic pumps infusing recombinant rat IL-33 (1 μg/kg/day) in normal pregnant (NP) and RUPP rats from gestation day 14-19. Maternal blood pressure, fetal growth, placental and renal ROS, phosphorylated endothelial nitric-oxide synthase ( p eNOS), and uterine artery resistance index (UARI) were assessed. MAP (mmHg) increased from 104±4 in NP to 124±7 in RUPP (p<0.05) and was significantly lowered in RUPP+IL-33 to 108±10 (p<0.05, n=6-8/group). Fetal weight was significantly increased in RUPP+ IL-33 compared to RUPP (p<0.05). Placental ROS was not different among any groups. However, renal ROS (relative light units/min/mg protein) was increased from 452±33 in NP to 676±44 in RUPP (p<0.05) and was significantly decreased to 309±61 in RUPP+IL-33 (n=4-5/group, p<0.05 vs RUPP). Placental p eNOS expression was 4-fold lower in RUPP vs NP (p<0.05) and 5-fold lower in RUPP+IL-33 vs NP, n=3-5/group). UARI (arbitrary units) was 0.709±0.012 in RUPP vs NP (0.585±0.025, p<0.05) and was significantly lowered to 0.577±0.025 in RUPP+IL-33 rats (p<0.05 vs RUPP, n=5-6/group). These findings demonstrate a role for IL-33 in controlling vascular function and maternal blood pressure during pregnancy independent of eNOS activation. Further studies will quantify effector immune cells and inflammatory cytokine levels in response to IL-33 supplementation during placental ischemia. These data suggest that IL-33 may have therapeutic potential in management of PE pathophysiology during pregnancy.