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Preeclampsia is a severe disorder of pregnancy for which there is no known cure, other than delivery, frequently involving very premature babies. The underlying cause of preeclampsia appears to involve the placenta, as most cases with preeclampsia resolve upon removal of the placenta. Furthermore, many cases of early onset severe preeclampsia are characterized by abnormal placental development. These pathologic changes involve the failure of invasive cytotrophoblast cells to adequately modify the maternal spiral arteries, thereby leading to an inadequate blood flow, resulting in placental hypoxia.The changes, however, may be more subtle, as is evident from the slightly altered villous structure in cases with preeclampsia. The villous tree is a unique tissue, in that it is covered by a single multinucleate cell layer, the syncytiotrophoblast. The syncytiotrophoblast has a surface area of many square meters, and is the source of a considerable amount of micro-debris, that is released into the maternal circulation. This material has been shown to have inflammatory characteristics, and can trigger a reaction by maternal immune cells. Recent studies have suggested that the maternal immune response to such placental particulate matter may be overtly strong. In neutrophils, this debris triggers a process termed netosis, whereby these cells release their DNA into the extracellular environment. Examinations of placental sections in cases with preeclampsia have shown that the inter-villous space is filled by neutrophils that have undergone netosis.The question therefore arises why more inflammatory placental micro-debris is released during preeclampsia, than in normal healthy pregnancies? One possible explanation is that the reduced blood flow in preeclampsia leads to abnormal syncytiotrophoblast development. This deregulation would then lead to the increased release of inflammatory micro-debris by this tissue, thereby triggering an overt maternal immune reaction.In order to study this facet in more detail, we plan to examine the molecular genetic pathways regulating the process of syncytialization, and then determine whether these are affected by conditions associated with preeclampsia, such as hypoxia. In this study we will focus on the potential role of miRNA molecules. This is because these unique small regulatory molecules, have been shown to play a key role in development and differentiation. Due to the complexity of placental tissue, we will first study in-vitro model systems, and then determine whether any key regulatory events we have detected, are pathologically altered in preeclamptic placentae.
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