Reduction in Regulatory T Cells in Early Pregnancy Causes Uterine Artery Dysfunction in Mice
Reduction in Regulatory T Cells in Early Pregnancy Causes Uterine Artery Dysfunction in Mice
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DOI：
10.1161/hypertensionaha.118.10858
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发表时间：
2018-07-01
期刊：
影响因子：
8.3
通讯作者：
Davidge, Sandra T.
中科院分区：
文献类型：
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作者：
Care, Alison S.;Bourque, Stephane L.;Davidge, Sandra T.
先兆子痫、胎儿生长受限和流产仍然是孕产妇和围产期发病率和死亡率的重要原因。这些并发症与母体循环、蜕膜和胎盘中称为调节性T细胞（Treg细胞）的特化T淋巴细胞亚群的数量减少有关。Treg细胞抑制炎症并阻止母体对胎儿的免疫力，胎儿表达外源的父亲同种异体抗原。Treg细胞被证明有助于血管稳态，但Treg细胞是否影响健康妊娠所必需的血管适应尚不清楚。因此，使用Treg细胞耗竭的小鼠模型，我们研究了Treg细胞耗竭将导致炎症增加和子宫动脉功能异常的假设。在这里，我们表明，Treg细胞耗竭导致胚胎吸收增加和促炎细胞因子的产生增加。平均动脉压在Treg细胞缺陷小鼠中表现出更大的NO调节，因为L-N-G-硝基精氨酸甲酯诱导的平均动脉压增加比Treg细胞充满小鼠高46%。子宫动脉功能，这是必不可少的营养供应给胎盘和胎儿，表现出失调的血液动力学后，Treg细胞耗竭。子宫动脉阻力和搏动指数增加，bET-1（大内皮素-1）转化为活性和强效血管收缩剂ET-1（内皮素-1）的转化增强，证明了这一点。这些数据表明Treg细胞在妊娠期间调节子宫动脉功能中的重要作用，并暗示Treg细胞对母体血管功能的控制是正常胎儿和胎盘发育的关键机制。
Preeclampsia, fetal growth restriction, and miscarriage remain important causes of maternal and perinatal morbidity and mortality. These complications are associated with reduced numbers of a specialized T lymphocyte subset called regulatory T cells (Treg cells) in the maternal circulation, decidua, and placenta. Treg cells suppress inflammation and prevent maternal immunity toward the fetus, which expresses foreign paternal alloantigens. Treg cells are demonstrated to contribute to vascular homeostasis, but whether Treg cells influence the vascular adaptations essential for a healthy pregnancy is unknown. Thus, using a mouse model of Treg-cell depletion, we investigated the hypothesis that depletion of Treg cells would cause increased inflammation and aberrant uterine artery function. Here, we show that Treg-cell depletion resulted in increased embryo resorption and increased production of proinflammatory cytokines. Mean arterial pressure exhibited greater modulation by NO in Treg cell-deficient mice because the L-N-G-nitroarginine methyl ester-induced increase in mean arterial pressure was 46% greater compared with Treg cell-replete mice. Uterine artery function, which is essential for the supply of nutrients to the placenta and fetus, demonstrated dysregulated hemodynamics after Treg-cell depletion. This was evidenced by increased uterine artery resistance and pulsatility indices and enhanced conversion of bET-1 (big endothelin-1) to the active and potent vasoconstrictor, ET-1 (endothelin-1). These data demonstrate an essential role for Treg cells in modulating uterine artery function during pregnancy and implicate Treg-cell control of maternal vascular function as a key mechanism underlying normal fetal and placental development.