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

先兆子痫（PE）是一种多系统妊娠疾病，影响5-8%的妊娠，是最常见的妊娠疾病之一

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.