More women die from pregnancy-related complications in the United States than in any other developed country and these rates are on the rise. Preeclampsia, a severe hypertensive syndrome, is a leading cause of these maternal deaths. The mechanisms triggering the development of preeclampsia are largely unknown, and currently, there is no cure for preeclampsia. Thus, there is an urgent need to identify pathogenic triggers of this syndrome and design interventions to counteract their actions. Based on published and preliminary data, we propose to test the working hypothesis that placental hypoxia/ischemia, a feature of pregnancies with preeclampsia, will cause the release of mtDNA via cell death-dependent mechanisms and that neutralizing circulating mtDNA will reduce the severity of the maternal syndrome in an experimental model of preeclampsia with placental ischemia. This hypothesis will be tested by the following aims. Aim 1: We will determine a potential mechanism by which trophoblast cells release mtDNA into the extracellular space. We hypothesize that placental ischemia will induce oxidative stress, which will contribute to trophoblast cell death and activation of autophagy, causing mtDNA release into the extracellular space. To address this aim, we will use human trophoblast cells and rat placental explants. Aim 2: We will determine the pathogenic role of circulating cell-free mtDNA in the development of preeclampsia-like symptoms in pregnant rats and the efficacy of a nucleic acid scavenger in reducing the severity of these symptoms. We hypothesize that an increase in concentrations of circulating mtDNA will precede the development of maternal hypertension and that neutralizing mtDNA with a nucleic acid scavenger will reduce concentrations of circulating mtDNA, alleviating preeclampsia-like symptoms in an animal model of preeclampsia. To address this aim, we will use integrative physiological approaches including: a) simultaneous continuous blood pressure recordings and mtDNA measurements before and after the induction of placental ischemia in pregnant rats, b) a mtDNA scavenger in an experimental model of preeclampsia with placental ischemia. Successful completion of the proposed studies will expand our understanding of the etiology of preeclampsia and may provide a pre-clinical foundation for the development of new interventions to neutralize circulating pro-inflammatory nucleic acids and improve maternal outcomes in pregnancies with preeclampsia.
|Program type||Transformational Project Award|
|Effective start/end date||07/01/2019 → 12/31/2019|