Abstract 31: Esomeprazole Improves Blood Pressure, Intrauterine Growth, Inflammation, And Vascular Function During Placental Ischemia Through Inhibition Of NLRP3

Abstract

Preeclampsia (PE), a multisystem hypertensive disorder of pregnancy is characterized by intrauterine growth restriction (IUGR), inflammation, and vascular dysfunction. NLRP3 inflammasome is a cytoplasmic complex that mediates inflammation and is implicated in CVD. Clinical studies show an association between PE and increased placental NLRP3 expression. We hypothesized that inhibition of NLRP3 using (1) a specific NLRP3 small molecule inhibitor, MCC950 (M9, 20 mg/kg/d, i.p.) or (2) esomeprazole (ESO, 3.5 mg/kg/d, oral), a therapeutic that is safe in pregnancy, would improve MAP, inflammation, IUGR, and vascular dysfunction in the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia. Sham (S) or RUPP surgery was performed in pregnant Sprague Dawley rats on gestation day (GD) 14. A subset of rats from both groups received either vehicle, M9, or ESO on GD14-19 (n=9/group). On GD18, Uterine Artery Resistance Index (UARI) was measured via Doppler Ultrasound. MAP, fetal, and placental weight were measured, and blood and tissues were processed for additional analyses on GD19. MAP (mmHg) was elevated in RUPP (133±1) vs S (108±2; p<0.05). Treatment with M9 or ESO in RUPP decreased MAP (111±1 and 115±3, respectively; p<0.05 vs RUPP). Fetal weight (g) was reduced in RUPP (2.1±0.04) vs S (2.4±0.05), and ESO normalized fetal weight (2.4±0.01; p<0.05 vs RUPP). Placental NLRP3 mRNA expression increased 5-fold in RUPP vs S (p<0.05); and was less than 2 fold in M9 and ESO treated RUPP rats (p<0.05 vs RUPP). Inflammatory T-helper 17 and cytolytic NK cells, evaluated by flow cytometry, were increased in the circulation, placenta, and kidney of RUPP vs S controls. Treatment with M9 or ESO normalized both cell populations in all tissues (p<0.05 vs RUPP). UARI was increased in RUPP (0.71±0.03) versus S (0.56±0.01; p<0.05) and was decreased to 0.48±0.01 in M9 and 0.61±0.03 in ESO-treated RUPPs (p<0.05 vs RUPP). Renal vascular resistance (mmHg/mL/min/g) was increased in RUPP (42±8) vs S (23±4, p<0.05) and was normalized to 26±3 after treatment with M9 (p<0.05 vs RUPP). These data implicate NLRP3 in mediating inflammation and vascular dysfunction to cause maternal HTN and IUGR in RUPP; and identify NLRP3 as a potential target and ESO as a potential therapeutic for PE.