Adriana and Luisa Castellucci award lecture 1999: role of oxygen in the regulation of trophoblast gene expression and invasion.

Changes in oxygen levels characterize normal and pathological human placentation. For example, relatively low Po(2)values are present around the blastocyst during implantation and in the placenta of the first trimester of pregnancy, a time of maximal trophoblast invasion. Our studies have revealed that low oxygen levels stimulate the in vitro invasiveness of cultured first trimester trophoblasts. This increased invasive ability is linked to elevated expression of some components of the plasminogen activator system and requires the participation of a putative haem protein. As gestation proceeds beyond the first trimester, and the extent of trophoblast invasion decreases, placental oxygen levels rise with a corresponding increase in blood flow. However, during certain pathological conditions, such as pre-eclampsia/intrauterine growth restriction, impaired remodelling of the uterine spiral arterioles leads to vessels with reduced diameters and localized regions of placental ischaemia/hypoxia. Placental hypoxia in the second half of gestation, as a consequence of reduced uteroplacental blood flow, may result in aberrant expression of genes that contribute to the pathophysiology of pre-eclampsia. Some of these genes encode certain cytokines and vasoactive molecules. We have also identified other genes whose expression is regulated by oxygen. Expression of one of them is induced in trophoblast and other cell types cultured under low oxygen levels and the product of the gene is a 43-kDa protein which we have termed PROXY-1. Compared to placental tissues and membranes isolated from uncomplicated pregnancies, PROXY-1 expression is elevated in tissues from pre-eclamptic pregnancies such as chorionic villi of peri-infarct regions, basal plate and membrane decidua, as well as chorion. Overall, these observations suggest that oxygen levels play an important role in placentation and in the pathophysiology of certain complications of pregnancy.