Investigation of the renin-angiotensin system at the maternal-fetal interface.

PROJECT SUMMARY There is evidence from human and animal studies that support that imbalance in the renin-angiotensin system (RAS), specifically reduced ACE2 protein levels and/or activity, leads to adverse maternal and fetal outcomes. Mouse dams and concepti with loss-of-function alleles of ACE2 exhibit increased embryonic loss, reduced fetal weight, placental hypoxia, and preeclampsia-like phenotypes in dams. While the RAS has been extensively studied in the kidney and circulation, much less is known about the local uterine and placental RAS early in pregnancy and if their disruption contributes to adverse maternal and fetal outcomes. Our proposed collaborative project will address this need, drawing on my expertise in embryo transfer techniques. The main objective of this innovative application is to test the hypothesis that ACE2 plays a local role at the maternal-fetal interface modulating normal placental development and fetal growth independent of the maternal circulating and kidney RAS. To test this hypothesis, we will conduct in-depth morphological phenotyping, novel RAS protein analyses, and blood pressure monitoring by radiotelemetry to determine the cell-specific contributions of ACE2 in the placenta (Aim 1) and decidua (Aim 2). These experiments will elucidate the function of the RAS that are relevant to idiopathic pregnancy loss and pregnancy complications. Given the known differences between mouse and human placentas, we will also determine RAS gene expression, protein abundance and localization in rhesus macaque placentas, which are more structurally similar to human (Aim 3). The Aims outlined in this application will provide extensive information for the field by improving understanding of the basic RAS function in utero- placental development during pregnancy. Determining the causes of pregnancy loss, and pregnancy complications would greatly improve human health, reducing the associated physiological, psychological, and economic burdens and help us shape advances in maternal-fetal medicine.