title: Role of Tumor Necrosis Factor-α and Natural Killer Cells in Uterine Artery Function and Pregnancy Outcome in the Stroke-Prone Spontaneously Hypertensive Rat.
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-α 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-α 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-α production and the reduction of granzyme B expression in CD161+natural killer cells in SHRSP.
authors.affiliation: From the BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Scotland (H.Y.S., R.N., H.M., E.B., T.J.G., D.G., C.D.); and Department of Internal Medicine, Jagiellonian University Medical College, Kraców, Poland (R.N.). h.small.1@research.gla.ac.uk.
authors.forename: Heather Yvonne
authors.initials: HY
authors.lastname: Small
authors.affiliation: From the BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Scotland (H.Y.S., R.N., H.M., E.B., T.J.G., D.G., C.D.); and Department of Internal Medicine, Jagiellonian University Medical College, Kraców, Poland (R.N.).
authors.forename: Ryszard
authors.initials: R
authors.lastname: Nosalski
authors.affiliation: From the BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Scotland (H.Y.S., R.N., H.M., E.B., T.J.G., D.G., C.D.); and Department of Internal Medicine, Jagiellonian University Medical College, Kraców, Poland (R.N.).
authors.forename: Hannah
authors.initials: H
authors.lastname: Morgan
authors.affiliation: From the BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Scotland (H.Y.S., R.N., H.M., E.B., T.J.G., D.G., C.D.); and Department of Internal Medicine, Jagiellonian University Medical College, Kraców, Poland (R.N.).
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Beattie
authors.affiliation: From the BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Scotland (H.Y.S., R.N., H.M., E.B., T.J.G., D.G., C.D.); and Department of Internal Medicine, Jagiellonian University Medical College, Kraców, Poland (R.N.).
authors.forename: Tomasz J
authors.initials: TJ
authors.lastname: Guzik
authors.affiliation: From the BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Scotland (H.Y.S., R.N., H.M., E.B., T.J.G., D.G., C.D.); and Department of Internal Medicine, Jagiellonian University Medical College, Kraców, Poland (R.N.).
authors.forename: Delyth
authors.initials: D
authors.lastname: Graham
authors.affiliation: From the BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Scotland (H.Y.S., R.N., H.M., E.B., T.J.G., D.G., C.D.); and Department of Internal Medicine, Jagiellonian University Medical College, Kraców, Poland (R.N.).
authors.forename: Christian
authors.initials: C
authors.lastname: Delles
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001783:Blood Flow Velocity; D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D000068800:Etanercept / Q000494:pharmacology; D005260:Female; D053804:Granzymes / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007694:Killer Cells, Natural / Q000378:metabolism*; D021041:Placental Circulation / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D011256:Pregnancy Outcome; D011270:Pregnancy, Animal; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012380:Role; D020521:Stroke / Q000503:physiopathology*; D055988:Uterine Artery / Q000187:drug effects / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D053804:Granzymes; D000068800:Etanercept
keywords: blood pressure determination; etanercept; hypertension; pregnancy outcome; uterine artery