Project Summary: Maternal obesity with increased circulating inflammatory markers can lead to adverse pregnancy outcomes, such as preeclampsia (PE). The clinical signs of PE include maternal hypertension and proteinuria during the second half of gestation. While PE presents later in pregnancy, its origins are thought to begin early in pregnancy or even before conception. Importantly, maternal hypertension only resolves after delivery of the placenta; therefore, it is widely accepted that abnormal placentation plays a causal role in PE pathogenesis, though the etiology of this is unknown. It is our hypothesis that maternal adiposity contributes to heightened inflammation and subsequent abnormal placental vascular development. The overarching goal of these proposed studies is to test the hypothesis that pro-inflammatory mediators produced by maternal adipose tissue (leptin) reduce pro- angiogenic immune cells and factors at the maternal-fetal interface. We will test our hypothesis in the BPH/5 mouse model of PE combining novel in vivo and ex vivo experiments. In Aim 1, we will determine if hyperleptinemia promotes decidual inflammation at the maternal-fetal interface in early pregnancy. Leptin- STAT3 inflammatory mediators will be measured in control+leptin mice and BPH/5 mice that have hyperleptinemia, which is attenuated with weight loss. In Aim 2, we will use single cell sequencing to isolate the source of decidual inflammation in these pregnancies as well as placental angiogenic deficiency. In Aim 3, offspring outcomes will be assessed to determine whether reversal of maternal obesity via pair-feeding prevents aberrant fetal cardiac angiogenesis and adult onset cardiometabolic dysfunction. These experiments will combine the gold standard radiotelemetric blood pressure recording with metabolic cages to ascertain cardiometabolic fitness in offspring when maternal hyperleptinemia is blunted and PE is prevented. These findings will provide groundbreaking prenatal mechanisms to prevent adult-onset cardiometabolic disease, hypertension, in PE born offspring.