A Role for Natural Killer Cells in the Development of Intrauterine Growth Restriction and Hypertension During Pregnancy

先兆子痫（PE）是一种多系统妊娠障碍，影响5-8%的妊娠，是其中之一。 全球孕产妇和胎儿发病率的主要原因。尽管经过几十年的研究，目前唯一的治疗方法 PE是胎儿和胎盘的早产，这往往有助于显着不良的胎儿 结果。因此，迫切需要更好地了解PE的病理生理学，以确定有效的 治疗目标临床研究发现，PE与主要的细胞溶解性 自然杀伤（NK）细胞免疫谱与正常妊娠相关的调节性NK谱。 此外，已经充分认识到蜕膜NK细胞的失调有助于复发性 流产和胎盘功能不全然而，细胞溶解性NK（cNK）细胞在肿瘤中的确切作用尚不清楚。 导致PE病理生理学的原因尚不清楚。本提案中概述的实验将提供更好的 了解cNK细胞可能介导PE病理生理学的机制。我们的动物模型 胎盘缺血的子宫灌注压降低（RUPP）大鼠模型概括了许多 先兆子痫妇女的特征，包括高血压，宫内生长受限， cNK活化和增殖。我们的初步数据表明，RUPP大鼠NK细胞的完全耗竭， 结果降低血压，减少氧化应激（ROS），并改善IUGR。我们还发现 RUPP大鼠中升高的TNF-α和IFN-γ在NK细胞刺激后显著降低， 耗尽这些数据支持NK细胞参与PE中的高血压和IUGR的假设。 然而，由于许多这些实验耗尽了整个NK细胞群体，我们仍然不能完全理解 cNK细胞在PE中的作用因此，我们计划使用过继转移技术来确定 胎盘缺血诱导的cNK细胞引起ROS增加和血管功能障碍， 妊娠期高血压和IUGR。我们还计划使用药理学抑制来阻断TNF-α和IFN-γ。 γ和评估RUPP大鼠的ROS产生、血管功能、高血压和IUGR的变化。基于 根据我们以前的数据，我们提出了胎盘缺血激活cNK细胞导致全身性 炎症和氧化应激，导致母体血管功能障碍、高血压和 妊娠期宫内生长受限。为了验证这一假设，我们将使用体内和体外 具体目的1：为了检验胎盘的假设， 缺血刺激的cNK细胞增加胎盘和肾ROS、炎性细胞因子（TNF-α和IFN-γ）， 血管功能障碍导致妊娠期高血压和IUGR。具体目标2：测试 胎盘缺血大鼠中阻断cNK相关细胞因子降低氧化应激的假设 和炎症导致改善血管功能，降低血压，减少IUGR， 怀孕

Preeclampsia (PE) is a multisystem pregnancy disorder that affects 5-8% of pregnancies and is one of the leading causes of maternal and fetal morbidity worldwide. Despite decades of research, currently the only cure for PE is premature delivery of the fetus and placenta, which often contributes significantly to poor fetal outcomes. Thus, there is an urgent need to better understand PE pathophysiology to identify effective therapeutic targets. Clinical studies have found that PE is strongly associated with a predominantly cytolytic Natural killer (NK) cell immune profile versus the regulatory NK profile associated with normal pregnancy. Furthermore, dysregulation of decidual NK cells has been well recognized to contribute to recurrent miscarriages and placental insufficiency. However, the precise role that cytolytic NK (cNK) cells play in contributing to PE pathophysiology is unknown. The experiments outlined in this proposal will provide a better understanding of the mechanisms by which cNK cells may mediate PE pathophysiology. Our animal model, the Reduced Uterine Perfusion Pressure (RUPP) rat model of placental ischemia, recapitulates many characteristics of preeclamptic women including hypertension, intrauterine growth restriction, and increased cNK activation and proliferation. Our preliminary data shows that total depletion of NK cells in RUPP rats results in lowered blood pressure, decreased oxidative stress (ROS), and improved IUGR. We have also found that both TNF-α and IFN-γ, which are increased in RUPP rats, are significantly decreased following NK cell depletion. These data support the hypothesis that NK cells contribute to hypertension and IUGR in PE. However as many of these experiments depleted the entire NK cell population, we still do not fully understand the role of cNK cells in PE. Therefore, we plan to use adoptive transfer techniques to determine the role of placental ischemia-induced cNK cells to cause increased ROS and vascular dysfunction leading to hypertension and IUGR in pregnancy. We also plan to use pharmacological inhibition to block TNF-α and IFN- γ and evaluate changes in ROS production, vascular function, hypertension and IUGR in RUPP rats. Based on our previous data, we propose the hypothesis that placental ischemia activates cNK cells leading to systemic inflammation and oxidative stress, which contribute to maternal vascular dysfunction, hypertension and intrauterine growth restriction during pregnancy. To test this hypothesis, we will use in vivo and in vitro techniques to examine the followings specific aims: Specific Aim 1: To test the hypothesis that placental ischemia stimulated cNK cells increase placental and renal ROS, inflammatory cytokines (TNF-α and IFN-γ), and vascular dysfunction leading to hypertension and IUGR in pregnancy. Specific Aim 2: To test the hypothesis that blockade of cNK associated cytokines in placental ischemic rats decreases oxidative stress and inflammation resulting in improved vascular function, lower blood pressure, and decreased IUGR during pregnancy.