Placental CD39 and CD73 in human pregnancy

During conditions of inadequate oxygen supply and necrosis, necrotic cells, as well as activated immune cells and endothelial cells release the nucleotide adenosine 5`-triphosphate (ATP). The released extracellular ATP serves as an important signalling molecule that modulates several pathological effects in the settings of inflammation, platelet activation and thrombosis. Extracellular ATP is deactivated by conversion into AMP and subsequently into adenosine by the two major nucleotide-metabolizing enzymes CD39 and CD73. In this project, the hypothesis is tested whether CD39 and CD73 are expressed in human placenta from very early phase onwards to term of gestation, and whether they are deregulated in response to pro-inflammatory cytokines, to reduced oxygen supply and increased mechanical shear forces. A protective role of CD39 and CD73 might be disturbed in pregnancy pathologies such as preeclampsia. Thus, this project aims to analyse three aspects. First, the spatial and temporal expression and enzymatic activity of CD39 and CD73 will be determined in human placenta. Thereafter, the placental CD39 and CD73 synthesis in response to platelet-derived factors, to inflammatory cytokines, or under conditions of low oxygen and shear forces is analysed. Furthermore, signalling pathways involved in deregulation of placental CD39 and CD73 are analysed. Finally, placental CD39 and CD73 synthesis is determined in pregnancies complicated by preeclampsia.

ATP, often referred to as the "energy currency" of the cell, can be released to the extracellular space, where it plays a role in various inflammatory and immune processes. This study investigated how levels of the two enzymes, CD39 and CD73, which are involved in the breakdown of extracellular ATP, change in the human placenta throughout pregnancy and in cases of the pregnancy disorder preeclampsia. The breakdown of extracellular ATP into the byproducts AMP and then adenosine helps to mitigate excessive inflammation, which is crucial during pregnancy. The key findings include that both enzymes are more expressed in preeclampsia, indicating a higher demand for ATP breakdown. In healthy pregnancy there is an increase in CD39 and a decrease in CD73 expression as pregnancy progresses. Oxygen levels do not affect enzyme levels, but factors released from maternal platelets can alter placental CD39 expression. In contrast factors like maternal smoking, fetal sex, maternal age, or BMI do not affect placental CD39 and CD73 levels. Mimicking increased CD39 levels in cells, by introducing additional copies of the gene, reduces extracellular ATP and inflammatory responses, highlighting its functional role in managing inflammation and coagulation at the placental interface. Overall, this study suggests that increased CD39 in the placenta might serve as a protective mechanism against inflammation and excessive coagulation, particularly in conditions like preeclampsia.