NLRP3 Inhibition Improves Maternal Blood Pressure, Inflammation, and Vascular Function During Placental Ischemia

Abstract

Preeclampsia (PE) is a pregnancy, hypertensive disorder with end‐organ damage, that develops after 20 weeks of gestation. PE pathophysiology often includes vascular dysfunction and increased inflammation that continues to damage patient health even after their PE resolves. Currently, there are no treatments for PE beyond delivery of the fetal‐placental unit. Previous clinical studies have identified elevated NLRP3 expression in PE placentas and suggest NLRP3 as a potential therapeutic target. In this study, we examined the effects of NLRP3 inhibition on PE pathophysiology in the reduced uterine perfusion pressure (RUPP) rat using MCC950 (20 mg/kg/day) or esomeprazole (3.5 mg/kg/day). We hypothesized that increased NLRP3 in response to placental ischemia impairs anti‐inflammatory IL‐33 signaling to induce T‐helper17 cell (TH17) and cytolytic NK cell (cNK) activation, which is known to mediate oxidative stress and vascular dysfunction causing maternal HTN and intrauterine growth restriction. RUPP rats had significantly higher placental NLRP3 expression, maternal blood pressure, fetal reabsorption rate, vascular resistance, oxidative stress, cNKs and TH17s, and decreased IL‐33 compared to normal pregnant (NP) rats. NLRP3 inhibition, with either treatment, significantly reduced placental NLRP3 expression, maternal blood pressure, fetal reabsorption rates, vascular resistance, oxidative stress, cNK and TH17 populations in RUPP rats. Based on our findings, NLRP3 inhibition reduces PE pathophysiology and esomeprazole may be a potential therapeutic for PE treatment.