Hypoxia and placental remodelling

In the first trimester of pregnancy fetal trophoblast cells invade the maternal uterine spiral arteries leading to loss of the vascular cells from the vessel wall and remodelling of the extracellular matrix. This is crucial to ensure that sufficient blood can reach the developing fetus. Impaired arterial remodelling is a feature of the major pregnancy pathologies pre-eclampsia and fetal growth restriction. Despite its importance, little is known about the regulation of this process. We have shown, using in vitro culture models and ex vivo explant models, that trophoblast cells play an active role in remodelling spiral arteries, and have implicated apoptotic events in this process. Further we have shown that trophoblast-derived factors such as Fas-ligand, tumor necrosis factor-related apoptosis inducing ligand (TRAIL) are important regulators of this process. The oxygen tension within the uteroplacental environment will vary with gestational age and will depend on the extent of trophoblast invasion and artery remodelling. Fluctuations in oxygen tension may be an important determinant of cellular events both during invasion towards uterine vessels and during the remodelling process. The components of this process known to be regulated by oxygen are reviewed, including lessons that can be learned from pregnancies at high altitude. In addition, data on the effect of varying oxygen tension on trophoblast production of pro-apoptotic factors and susceptibility of vascular smooth muscle cells to induction of apoptosis are described.