Integrating Environmental Cues at the Maternal-Fetal Vascular Interface

Most indicated preterm deliveries occur due to ischemic placental diseases processes such as preeclampsia (PE) and intrauterine growth restriction (IUGR). The maternal-fetal interface in these conditions is characterized by a set of pathological findings collectively referred to as maternal vascular underperfusion (MVU). The exact etiologies remain unclear, but poor trophoblast invasion and incomplete remodeling of the spiral arteries, with impaired trophoblast differentiation, have been implicated. Importantly, environmental factors such as oxygen tension can significantly modulate placental development and contribute to ischemic placental disease pathogenesis, in part, via activation of Hypoxia-inducible Factor-dependent gene expression. One of the most severe forms of environmental manipulation occurs during in vitro fertilization (IVF). The goals of this project are to define HIF-1 and -2 dependent transcriptional effects on trophoblast differentiation and metabolism, and to determine how they are impacted by IVF status in rodent models as well as human pregnancies. The collective expertise of the investigators involved uniquely positions us to advance our understanding of the metabolic drivers and consequences of ischemic placental disease processes, how IVF methodologies synergize with them, and identify novel targets for pharmacologic and/or metabolic intervention.