IL-33 supplementation improves vascular function and maternal hypertension in response to placental ischemia
Authors: Wang Xi , Shields Corbin , Tardo Geilda , Peacock Greg , Williams Jan , Cornelius Denise 
Published: May 2023

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, inflammation, 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) into normal pregnant (NP) and RUPP rats from gestation day 14-19. Maternal blood pressure, fetal growth, cytolytic NK (cNK) and TH17 populations, placental and renal ROS, placental vascular endothelial growth factor (VEGF), phosphorylated endothelial nitric-oxide synthase (peNOS), and uterine artery resistance index (UARI) were assessed. MAP (mmHg) increased from 104±4 in NP to 124±7 in RUPP (p<0.05vsNP) and was lowered in RUPP+IL-33 to 108±10 (p<0.05vsRUPP, n=8/group). Fetal weight decreased from 2.0±0.2g in NP to 1.36±0.1g in RUPP (p<0.05, n=8/group) and increased to 2.17±0.1g in RUPP+ IL-33 (p<0.05vsRUPP). Circulating cNKs (% gated) increased from 0.9±0.2% in NP to 3.9±1.1% in RUPP (p<0.05vsNP, n=8/group) and decreased to 1.1±0.6% in RUPP+IL-33 (p<0.05 vs RUPP). Circulating TH17s (%CD4+ T cells) increased from 1.0±0.6% in NP to 7.2±0.5% in RUPP (p<0.05 vs NP) and decreased to 0.8 ±0.4% in RUPP+IL-33 (p<0.05vsRUPP). Placenta cNKs and TH17s also followed these trends though no significant differences were seen in renal cNKs and TH17s. 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<0.05vsNP) and was significantly decreased to 309±61 in RUPP+IL-33 (p<0.05vsRUPP, n=4-5/group). Placental VEGF (pg/mg protein) decreased from 43.2±2.7 in NP to 18.5±5.6 in RUPP (p<0.05vsNP) and was not changed in RUPP+IL-33. Placental peNOS 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 0.585±0.025 in NP (p<0.05) and was significantly lowered to 0.577±0.025 in RUPP+IL-33 rats (p<0.05vsRUPP, n=5-6/group). These findings demonstrate a role for IL-33 in controlling vascular function and maternal blood pressure during pregnancy independent of VEGF/eNOS signaling. Further studies will quantify inflammatory cytokine levels and NO bioavailability 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. This research was supported by funding from the following NIH grants: F31HL165851 (XW), T32HL105324 (CS), R01DK109133 (JW), and R01HL151407 (DC). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.