Abstract 022: Il-33 Supplementation Improves Vascular Function And Maternal Hypertension In Response To Placental Ischemia

Abstract

Preeclampsia (PE), a leading cause of maternal/fetal morbidity and mortality, is a hypertensive pregnancy disorder with end-organ damage that manifests after 20 weeks of gestation. PE is characterized by chronic immune activation and endothelial dysfunction. Clinical studies report reduced IL-33 signaling in PE. We use the R educed U terine P erfusion P ressure (RUPP) rat model, which mimics many PE characteristics including reduced IL-33, to identify mechanisms mediating PE pathophysiology. We hypothesized IL-33 supplementation would improve blood pressure (BP), inflammation, and oxidative stress (ROS) during placental ischemia. We implanted i.p. mini-osmotic pumps infusing recombinant rat IL-33 (1 μg/kg/day) into normal pregnant (NP) and RUPP rats from gestation day 14-19. We assessed maternal BP, cytolytic NK (cNK) and T H 17 cells, cNK cell activity, ROS, preproendothelin-1 (PPET) expression, and uterine artery resistance index (UARI). MAP (mmHg) was 104±4 in NP vs 124±7 in RUPP (p<0.05 vs NP) and lowered to 108±10 in RUPP+IL-33 (p<0.05 vs RUPP, n=8/group). Circulating cNKs (% gated) were 0.9±0.2% in NP vs 3.9±1.1% in RUPP (p<0.05 vs NP) and decreased to 1.1±0.6% in RUPP+IL-33 (p<0.05 vs RUPP, n=8/group). Circulating T H 17s (%CD4 + T cells) were 1.0±0.6% in NP vs 7.2±0.5% in RUPP (p<0.05 vs NP) and 0.8±0.4% in RUPP+IL-33 (p<0.05 vs RUPP, n=8/group). Renal T H 17s, placenta cNKs and T H 17s followed similar trends. cNK cell activity (fold change) was 3.92±0.6 fold higher in RUPP vs NP (p<0.05 vs NP) and decreased to -0.24±0.1 in RUPP+IL-33 (p<0.05 vs RUPP, n=3/group). Renal ROS (relative light units/min/mg protein) was 452±33 in NP vs 676±44 in RUPP (p<0.05) and decreased to 258±50 in RUPP+IL-33 (p<0.05 vs RUPP, n=5/group). Placental PPET (fold change) was 2.36±0.4 fold higher in RUPP vs NP (p<0.05) and decreased to 1.22±0.2 in RUPP+IL-33 (p=0.05 vs RUPP, n=6-7/group). UARI (arbitrary units) was 0.71±0.01 in RUPP vs 0.54±0.01 in NP (p<0.05) and was lowered to 0.57±0.02 in RUPP+IL-33 (p<0.05 vs RUPP, n=6/group). These findings demonstrate a role for IL-33 in controlling vascular function and maternal BP during pregnancy by decreasing inflammation, ROS, and PPET expression. These data suggest IL-33 may have therapeutic potential in managing PE.