Investigation of the role of uterine NK cells in initiation of spiral artery transformation in normal human pregnancy

螺旋动脉是子宫内将母体血液输送到胎盘和婴儿的血管。在正常妊娠早期，这些血管的结构发生了根本性的变化（称为“转化”或“重塑”）。螺旋状动脉变宽，动脉壁结构改变，通常构成动脉壁的厚肌肉消失。这个过程的最终结果是螺旋状动脉能够运输胎盘和婴儿所需的额外血液和氧气。子宫螺旋动脉的这些变化是成功怀孕的必要条件。如果这个过程没有发生，那么并发症，如晚期流产，胎儿生长受限（小婴儿），早产和先兆子痫（高血压，尿蛋白和母亲水肿）可能发生。尽管它对成功的结局很重要，但对于正常妊娠中子宫内螺旋动脉改变的过程所知甚少。在怀孕的前半期，胎盘细胞（滋养细胞）侵入螺旋动脉，长期以来人们认为子宫螺旋动脉的变化是由这些细胞引起的。然而，最近发现，在胎盘滋养层细胞出现之前，血管壁的结构就已经发生了初步的变化。来自小鼠妊娠期的证据表明，这些最初的变化是由一种特殊的白细胞类型介导的，这种白细胞类型在妊娠早期大量存在于子宫内膜；这些细胞被称为子宫自然杀伤细胞。我们在螺旋状动脉壁上看到的一些变化与在现有血管生长的早期阶段所看到的变化相似，这一过程被称为血管生成。关于血管生成与癌症的关系，我们已经做了很多工作，所以我们知道在这个过程的不同步骤中涉及的许多因素。因此，我们知道哪些因素可能参与了我们在子宫血管中看到的变化。在之前的一项研究中，我们已经表明子宫自然杀伤细胞是子宫中大多数关键因素的主要来源。我们也证明了这些细胞的数量在那些有小婴儿或子痫前期的妇女的子宫里更少因为这些子宫里螺旋动脉的重塑是有缺陷的。因此，我们想进一步探讨这种细胞类型在启动子宫螺旋动脉重塑中的作用。我们计划使用多种技术来实现这一目标。我们将使用妊娠早期从胎盘和底层子宫内膜取出的组织以及实验室血管重塑模型。首先，我们将检查正常妊娠的子宫组织，以准确确定螺旋动脉壁结构在重塑过程的早期阶段发生了什么变化。然后我们将继续使用血管的实验室模型和组成血管的细胞，并试图找出子宫自然杀伤细胞是如何发挥作用的。我们希望通过提高我们对正常妊娠中螺旋动脉重塑的启动和控制过程的理解，我们将能够理解并尝试治疗变得复杂的妊娠。

Spiral arteries are the blood vessels in the womb that transport maternal blood to the placenta and baby. Early in a normal pregnancy these blood vessels undergo radical changes in their structure (termed 'transformation' or 'remodeling'). The spiral arteries become wider and the structure of the wall is altered so that the thick muscle which normally makes up the artery wall is lost. The end result of this process is that the spiral arteries are able to transport the extra blood and oxygen which is needed for the placenta and baby. These changes in the spiral arteries of the womb are necessary for a successful pregnancy outcome. If this process does not occur then complications such as late miscarriage, fetal growth restriction (small babies), premature labor and preeclampsia (high blood pressure, protein in urine and oedema in the mother) can occur. Despite its importance for a successful outcome, very little is known about the process by which the spiral arteries in the womb are altered in normal pregnancy. During the first half of pregnancy cells from the placenta (trophoblast cells) invade the spiral arteries and it was thought for a long time that the changes in the uterine spiral arteries were due to these cells. Recently, however, it has become apparent that there are initial changes in the structure of the vessel wall which occur before the placental trophoblast cells are present. Evidence from mouse pregnancy indicates that these initial changes are mediated by a specialist white blood cell type which is present in large numbers in the lining of the womb in early pregnancy; these cells are called uterine natural killer cells. Some of the changes that we see in the spiral artery walls are similar to those seen during the early stages of growth of new blood vessels from existing ones, a process known as angiogenesis. There has been a lot of work on angiogenesis in relation to cancer and so we know many of the factors that are involved in the different steps of this process. Therefore, we know which factors are likely to be involved in initiating the changes we see in the blood vessels of the uterus. In a previous study we have shown that the uterine natural killer cells are the major source of most of these key factors in the uterus. We have also shown that numbers of these cells are lower in the womb of women who have small babies or preeclampsia where the remodeling of the spiral arteries is deficient. Therefore, we want to further explore the role of this cell type in initiating remodeling of the uterine spiral arteries. We plan to do this using a combination of techniques. We will use tissue taken from the placenta and the underlying uterine lining during early pregnancy as well as models of vessel remodeling in the laboratory. Initially we will examine tissues from the uterus of normal pregnancies in order to determine precisely what changes occur in the structure of the spiral artery wall in the early stages of the remodeling process. We will then go on to use laboratory models of vessels and the component cells which make up the vessels and try to find out how the uterine natural killer cells have their effect. We hope that by improving our understanding of the processes which start and control spiral artery remodeling in normal pregnancy we will then be able to understand and try to treat pregnancies that become complicated.