The role of decidual natural killer cells in pregnancy

Abstract

During pregnancy, maternal uterine spiral arteries are remodelled from minimal flow, high resistance vessels into large diameter, low resistance, high flow vessels. This change is crucial for delivery of adequate blood supply to the developing fetus, and is impaired in pregnancies complicated by pre-eclampsia. In early pregnancy, fetal trophoblasts invade into the decidua and remodel the spiral arteries. However, decidual natural killer (dNK) cells accumulate around spiral arteries and are present ahead of trophoblast invasion. Their presence is continuous during trophoblast invasion and spiral artery remodelling. A functional role for dNK in remodelling has not yet been defined. Measurement of uterine artery resistance indices (RI), by Doppler ultrasound at 9-14 weeks of gestation, was used to identify pregnancies with 21 % risk (high RI). Following surgical termination of pregnancy, CD56+ dNK cells were isolated and comparisons made between cells from normal and high RI pregnancies. dNK cell-secreted factors and receptor expression were characterised by proteome profiler arrays, multiplex assays, flow cytometry and western blot analysis. Differences between the two groups were detected in several factors, including angiogenin, endostatin, hepatocyte growth factor (HGF), placental growth factor (PIG F), the soluble interleukin-2 receptor (sIL-2R), active matrix metalloproteinases (MMPs), tumour necrosis factor (TNF)-α, Fas ligand (FasL) and TNF-related apoptosis inducing ligand (TRAIL). dNK effects on trophoblasts and vascular cells were investigated by eo- culture studies to model the interactions at the maternal-fetal interface. Normal RI dNK solube factors were able to promote trophoblast motility (an important component of invasion), to a greater extent than high RI dNK, and a function for dNK-secreted HGF in promoting trophoblast motility was determined. Normal RI dNK caused destabilisation of endothelial cell tube-like structures, partly through TNF-α, whereas this effect was not seen with high RI dNK. Normal RI dNK cells also induced vascular cell apoptosis partly via FasL, while high RI dNK cells did not. These studies demonstrate a functional role for dNK in regulating trophoblast motility and vascular cell remodelling, events of importance in a successful pregnancy. The ability of dNK to regulate these events in pregnancies at higher risk of pre-eclampsia is impaired, which may contribute to the poor remodelling seen in these pregnancies.EThOS - Electronic Theses Online ServiceGBUnited Kingdo