The role of tumor necrosis factor-α and natural killer cells in uterine artery function and pregnancy outcome in the stroke prone spontaneously hypertensive rat

Small, H. Y., Nosalski, R., Morgan, H., Beattie, E., Guzik, T., Graham, D. and Delles, C. (2016) The role of tumor necrosis factor-α and natural killer cells in uterine artery function and pregnancy outcome in the stroke prone spontaneously hypertensive rat. Hypertension, 68(5), pp. 1298-1307. (doi:10.1161/HYPERTENSIONAHA.116.07933) (PMID:27733586) (PMCID:PMC5058643)

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Abstract

Women with chronic hypertension are at increased risk of maternal and fetal morbidity and mortality. We have previously characterized the stroke-prone spontaneously hypertensive rat (SHRSP) as a model of deficient uterine artery function and adverse pregnancy outcome compared with the control Wistar–Kyoto. The activation of the immune system plays a role in hypertension and adverse pregnancy outcome. Therefore, we investigated the role of tumor necrosis factor-[alpha] in the SHRSP phenotype in an intervention study using etanercept (0.8 mg/kg SC) at gestational days 0, 6, 12, and 18 in pregnant SHRSP compared with vehicle-treated controls (n=6). Etanercept treatment significantly lowered systolic blood pressure after gestational day 12 and increased litter size in SHRSP. At gestational day 18, etanercept improved the function of uterine arteries from pregnant SHRSP normalizing the contractile response and increasing endothelium-dependent relaxation, resulting in increased pregnancy-dependent diastolic blood flow in the uterine arteries. We identified that the source of excess tumor necrosis factor-[alpha] in the SHRSP was a pregnancy-dependent increase in peripheral and placental CD3– CD161+ natural killer cells. Etanercept treatment also had effects on placental CD161+ cells by reducing the expression of CD161 receptor, which was associated with a decrease in cytotoxic granzyme B expression. Etanercept treatment improves maternal blood pressure, pregnancy outcome, and uterine artery function in SHRSP by antagonizing signaling from excess tumor necrosis factor-[alpha] production and the reduction of granzyme B expression in CD161+ natural killer cells in SHRSP.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nosalski, Mr Ryszard and Graham, Dr Delyth and Morgan, Miss Hannah and Delles, Professor Christian and Beattie, Mrs Elisabeth and Guzik, Professor Tomasz
Authors: Small, H. Y., Nosalski, R., Morgan, H., Beattie, E., Guzik, T., Graham, D., and Delles, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Hypertension
Publisher:American Heart Association
ISSN:0194-911X
ISSN (Online):1524-4563
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Hypertension 68(5):1298-1307
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
492454BHF 4 Year PhD ProgrammeAnna DominiczakBritish Heart Foundation (BHF)FS/12/66/30003RI CARDIOVASCULAR & MEDICAL SCIENCES
595241Cardiovascular consequences of preeclampsia in women from the Generation Scotland: Scottish Family Health Study.Christian DellesScottish Executive Health Department (SEHHD-CSO)ETM/196RI CARDIOVASCULAR & MEDICAL SCIENCES