Intrauterine growth restriction (IUGR), defined as failure of the fetus to achieve its genetically determined growth potential, complicates 4-7% of births and is linked to a 6 to 10 fold increased risk of perinatal mortality. Low placental oxygenation is believed to play a pivotal role in the development of IUGR based on observations indicating increased expression of genes regulated by hypoxia in placentae of IUGR pregnancies.

Endoglin is a cell-surface co-receptor for transforming growth factor (TGF)-ß1 and TGF- ß3 isoforms and is highly expressed in endothelial cells and syncytiotrophoblasts. It has been shown that endoglin plays a key regulatory role in the process of trophoblast differentiation along the invasive pathway. Recent evidence has indicated that in preeclamptic placentae endoglin expression is elevated, and this is associated with high circulatory levels of its soluble form (sENG). It has been hypothesized that sENG may act in concert with soluble VEGF receptor 1 (sFlt1) to induce severe preeclampsia. We have previously reported that TGFß3 expression is regulated by oxygen and is high in pre-eclamptic pregnancies.

The goal of this project is to determine the role of oxygen and TGFß in regulating the expression of endoglin in the human placenta and to characterize endoglin expression in physiological and pathological models of placental hypoxia.

We will examine placentae from different stages of development, knowing that early placentation occurs in poorly oxygenated environment and at 10-12 weeks there is an increase in oxygen tension. In addition, as a pathological model of placental hypoxia we will use placentae of IUGR pregnancies including both IUGR singletons and discordant twins, in which the normal co-twin serves as a control of the IUGR discordant twin. We believe that the pathology in the IUGR discordant twin truly represents a placental disease since both twins are exposed to the same maternal environment.

We believe that findings of this project will introduce new data regarding the regulation of endoglin in the human placenta and will contribute to the understanding of the pathogenesis of IUGR.