Interferon γ neutralization reduces blood pressure, uterine artery resistance index, and placental oxidative stress in placental ischemic rats

Abstract

Preeclampsia (PE) is characterized by maternal hypertension, intrauterine growth restriction, increased cytolytic natural killer cells (cNKs), which secrete interferon gamma (IFNγ). However, the precise role of IFNγ in contributing to PE pathophysiology remains unclear. Using the Reduced Uterine Perfusion Pressure (RUPP) rat model of placental ischemia, we tested the hypothesis that neutralization of IFNγ in RUPPs will decrease placental reactive oxygen species (ROS) and improve vascular function resulting in decreased MAP and improved fetal growth. On Gestation Day (GD) 14, the RUPP procedure was performed and on GDs 15 and 18, a subset of normal pregnant rats (NP) and RUPP rats were injected with 10μg/kg of an anti rat-IFNγ monoclonal antibody. On GD18, Uterine Artery Resistance Index (UARI) was measured via Doppler Ultrasound and on GD19, mean arterial pressure (MAP) was measured, animals were sacrificed, and blood and tissues were collected for analysis. Increased MAP was observed in RUPP rats compared to NP and was reduced in RUPP+anti-IFNγ. Placental ROS was also increased in RUPP rats compared to NP and was normalized in RUPP+anti-IFNγ. Fetal and placental weights were reduced in RUPP rats, but were not improved following anti-IFNγ treatment. However, UARI was elevated in RUPP compared to NP and was reduced in RUPP+anti-IFNγ. In conclusion, we observed that IFNγ neutralization reduced MAP, UARI, and placental ROS in RUPP recipients. These data suggest that IFNγ is a potential mechanism by which cNKs in contribute to PE pathophysiology and may represent a therapeutic target to improve maternal outcomes in PE.

Dark Sweet Cherry (Prunus avium) Supplementation Reduced Blood Pressure and Pro-Inflammatory Interferon Gamma (IFNγ) in Obese Adults without Affecting Lipid Profile, Glucose Levels and Liver Enzymes

“…Findings from this study demonstrated that anthropometric (BW and BMI) and HR values as well as IFNγ worsened in the placebo group, accompanied by the counteracting response of increased anti-inflammatory IL-10 and IL-1RA, while in the cherry group these variables remained unchanged over the DSC intervention. A positive and significant correlation between changes in SBP and IFNγ in the cherry group suggests that DSC-mediated IFNγ downregulation contributed to reduce SBP with implications for improved vascular function, as previously reported [ 44 ].…”

Stable adrenomedullin analog mitigates placental ischemia-induced hypertension and fetal growth restriction in rats

“…In RUPP rodents, the number and size of uterine spiral arterioles decreases and the expression of MMP-2 and MMP-9 in uterus and uterine arteries is lower. Several therapeutic candidates, including 17-alpha-hydroxyprogesterone, pravastatin, sildenafil, interleukin (IL)-10, vitamin D, placental growth factor, relaxin, liraglutide, sonic hedgehog protein, low dose IL-2, IL-25, an angiotensin II type 1 receptor autoantibody blockade peptide, Etanercept, a hydrogen sulfide releasing molecule MZe786, l -(+)-ergothioneine, a soluble IL-17 receptor IL-17RC, and apelin, as well as interferon γ neutralization, have been found to reduce hypertension in RUPP animals to varying degrees [78–96]. However, only a few candidates, such as IL-25, Etanercept, IL-17RC, and MZe786, have been found to significantly mitigate FGR in RUPP animals [92–95].…”

“…The RUPP model is characterized by placental ischemia, maternal endothelial dysfunction, and increased vascular resistance and stiffness [75][76][77]. It was used to evaluate the translational potential of various therapeutic candidates on pregnancy-associated hypertension and fetal growth restriction [78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96]. Although this rodent model is not ideal for modeling preeclampsia in humans, this proof-of-concept study demonstrated that ADE101 could be a promising candidate for improving vascular homeostasis in patients with pregnancy-associated hypertension and fetal growth restriction.…”

The central role of natural killer cells in preeclampsia

“…In rats with placental ischemia, the removal of NK cells reduces blood pressure by inhibiting TNF-α signaling. In addition, IFN-γ is an essential contributor to the etiology of PE caused by cNK cells and may be used as a therapeutic target to alleviate PE symptoms ( 135 ). Significantly elevated IFN-γ was secreted by NK cells in the peripheral blood of women with severe PE, and this elevation was associated with syncytiotrophoblast microparticles from the placenta ( 136 ).…”