Succinate as Signaling Molecule in Human Placenta

Placental dysfunction is present in pregnancy pathologies such as gestational diabetes mellitus. An important aspect of placental functionality is metabolic flexibility which allows the tissue on the one hand to adapt to developmental changes and on the other hand to respond to stress. Thus, if placental metabolic reprograming fails, this can result in pregnancy complications such as preeclampsia. Furthermore, new evidence suggests that metabolic products can accumulate and cause diverse alterations in cell function. In parallel, our previous results showed increased succinate concentrations in whole placental lysates from gestational diabetes patients relative to healthy controls. Within the proposed project, we aim to address the hypothesis that succinate is a major signal transducer in human placenta and has important implications in serious pregnancy pathologies such as preeclampsia and gestational diabetes. We have recently shown that the succinate receptor is expressed in human placental endothelial cells. Thus, in this study we will focus on elucidating the functional and mechanistic responses to succinate and activation of its receptor in these cells. This project will thus generate novel insights into dysregulation in this signaling axis, which might be a previously unexplored pathogenic mechanism in preeclampsia and gestational diabetes.