Small Heather Yvonne, Nosalski Ryszard, Morgan Hannah, Beattie Elisabeth, Guzik Tomasz J, Graham Delyth, Delles Christian
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.).
Hypertension. 2016 Nov;68(5):1298-1307. doi: 10.1161/HYPERTENSIONAHA.116.07933. Epub 2016 Oct 10.
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.
患有慢性高血压的女性发生孕产妇和胎儿发病及死亡的风险增加。我们之前已将易患中风的自发性高血压大鼠（SHRSP）描述为与对照Wistar-Kyoto相比子宫动脉功能缺陷和不良妊娠结局的模型。免疫系统的激活在高血压和不良妊娠结局中起作用。因此，在一项干预研究中，我们在妊娠第0、6、12和18天给怀孕的SHRSP注射依那西普（0.8mg/kg皮下注射），与接受载体治疗的对照组（n = 6）相比，研究肿瘤坏死因子-α在SHRSP表型中的作用。依那西普治疗显著降低了妊娠第12天后的收缩压，并增加了SHRSP的产仔数。在妊娠第18天，依那西普改善了怀孕SHRSP的子宫动脉功能，使收缩反应正常化并增加了内皮依赖性舒张，导致子宫动脉中与妊娠相关的舒张期血流增加。我们确定SHRSP中过量肿瘤坏死因子-α的来源是外周和胎盘CD3 CD161自然杀伤细胞中与妊娠相关的增加。依那西普治疗还通过降低CD161受体的表达对胎盘CD161细胞产生影响，这与细胞毒性颗粒酶B表达的降低有关。依那西普治疗通过拮抗过量肿瘤坏死因子-α产生的信号传导以及减少SHRSP中CD161自然杀伤细胞中颗粒酶B的表达，改善了SHRSP的母体血压、妊娠结局和子宫动脉功能。
