Role of angiogenic Notch in uterine decidualization and placentation

? DESCRIPTION (provided by applicant): Preeclampsia (PE), a disease caused by vascular disorders in the placenta, affects 3-7% of pregnancies, resulting in increased neonatal and maternal morbidity and mortality. PE is responsible for 15% of preterm births and is the second largest cause of maternal mortality worldwide. Consequences of PE include maternal hypertension and renal dysfunction, fetal growth restriction, preterm birth, and even perinatal death. Mothers and offspring who have survived a PE pregnancy, have increased risk for long-term cardiovascular disease. NOTCH protein expression is altered in PE placentas and Notch2 deletion in mouse trophoblasts results in poor placental perfusion, a characteristic of PE. Thus, Notch is implicated in the pathogenesis of PE, yet the roles of Notch in uterine and placental vascular formation have not been fully investigated. In order to improve our understanding of physiologic uterine and placental vascular formation and the pathogenesis of PE, this study investigates Notch signaling in mouse PE models and human PE samples. We found that Notch signaling is active in the murine decidual vasculature that functions to support embryonic growth and development prior to placenta formation. In the placenta, we found that Notch signaling is active in both endothelial cells and trophoblasts, with distinct Notch protein and ligand expression. We hypothesize that Notch signaling regulates decidual angiogenesis and placental vascular formation and that disruption of Notch causes adverse pregnancy outcomes, including early miscarriages and PE. Genetic interventions in mice will be performed to define Notch function in the differentiation of placental endothelial cells and trophoblasts. We will evaluate P mouse models and human PE placental tissues for changes in Notch signaling. We present a novel approach to understanding the pathogenesis of PE and our study lays the foundation for developing tools to aide in early detection and/or management of PE and reduction of cardiovascular risk.