Maternal vascular responses to extracellular mitochondrial DNA during pregnancy

项目总结

PROJECT SUMMARY Hypertensive disorders of pregnancy, including preeclampsia, are among the leading causes of maternal deaths. It has been suggested that in preeclampsia, placental hypoperfusion/ischemia results in release of pro- inflammatory factors that interact with the maternal vascular wall to induce maternal vascular dysfunction and hypertension. The molecular pathways linking placenta-derived factors and maternal vascular dysfunction are not understood. Furthermore, the mechanisms determining the release of placenta-derived factors in the maternal circulation are underexplored. The proposed studies will address these knowledge gaps by testing the role of extracellular mitochondrial DNA (mtDNA) as a novel link between maternal vascular dysfunction and placental ischemia, common features of preeclampsia. Plasma from women with preeclampsia has increased circulating cell-free mtDNA, which has been shown to be immunogenic and pro-inflammatory in various inflammatory conditions. Furthermore, clinical studies have demonstrated a positive association between circulating mtDNA and the risk of developing preeclampsia. Here, we propose that circulating cell-free mtDNA derived from the placenta is a major contributor to maternal vascular dysfunction in preeclampsia, due in part to its effects on Toll-like receptor 9 (TLR-9). Aim 1: we will determine a molecular mechanism linking extracellular mtDNA with maternal vascular dysfunction during pregnancy. We hypothesize that vascular exposure to extracellular mtDNA will induce an increase in maternal vascular tone through activation of TLR-9 signaling. This hypothesis will be tested using an integrative approach involving isolated maternal arteries, vascular cells, and an in vivo mtDNA challenge in healthy non-pregnant and pregnant rats. Aim 2: we will determine a potential mechanism by which placental hypoxia induces release of mtDNA. We will test the hypothesis that placental hypoxia causes increased generation of reactive oxygen species, which in turn triggers the release of mtDNA into the extracellular space by inducing cell death and increasing autophagy. To address this hypothesis, we will use human trophoblast cells and rat placental explants. Aim 3: we will determine whether increased circulating mtDNA is involved in the pathogenesis or maintenance of the maternal cardiovascular syndrome in preeclampsia. We will test the hypothesis that increased circulating mtDNA triggers the maternal cardiovascular syndrome in an animal model with placental ischemia that mimics clinical end-points of preeclampsia and has higher concentrations of circulating mtDNA compared to normal pregnant rats. This research may have a translational impact because it will provide a pre-clinical platform for the development of pharmacological strategies to reduce mtDNA release, neutralize extracellular mtDNA, or inhibit TLR-9 in those women who have high concentrations of circulating cell-free mtDNA during pregnancy.