To establish the feto-maternal exchange in human placental development transient physiological hypoxia is mandatory. This condition ensures that fetal cytotrophoblast stem cells differentiate and invade into the uterine arterioles where they support extensive angiogenesis to supply the fetus. This endovascular invasion is disrupted in a disease called preeclampsia (in up to 10% of all pregnancies) and results in chronic hypoxia. Since it is known that gap junction proteins (connexins) are directly involved in human trophoblast cell-cell communication, fusion, differentiationand invasion, we began to study their physiological and pathophysiological behaviour under different oxygen supply in dependency of transcription factors Hypoxia Inducible Factors.

In this study we were able to show that in the trophoblast model cell line JAr connexin 43 (important for fusion and differentiation) was internalized during hypoxia, depending on hypoxia inducible factor 2. In contrast connexin 46 (which is anti-apoptotic during hypoxia) translocated from nucleus adjacent areas to the cell membrane. Both hypoxia mediated translocations were reversible after reoxygenation. Functional studies of cell coupling analysed by calcein dye transfer using flow cytometry showed a significant decrease in cell coupling under hypoxia compared to normoxic conditions. Severe preeclamptic placenta samples (week of gestation 25–34) showed a strongly enhanced connexin 43 protein level and a diminished connexin 46 protein level.

To summarize, this study showed that placental connexins Cx43 and Cx46 are hypoxia-regulated and are associated with loss in function which could contribute to the pathomechanisms in preeclampsia.