PROJECT SUMMARY The goal of this proposal is to identify the mechanistic link between fetal glucagon and placental nutrient delivery as a novel, adaptive mechanism for matching nutrient supply to fetal metabolic demand under adverse uterine conditions. Pregnancies complicated by intrauterine acidosis, hypoxia, and growth restriction are often characterized by elevated fetal glucagon. While fetal metabolic hormones have historically been considered for their function in regulating fetal growth, recent evidence from the Rozance laboratory has suggested glucagon may be regulating maternal nutrient delivery via placental signaling. In nine-day fetal glucagon infusions in sheep, we observed dramatically reduced uterine blood flow which resulted in decreased placental transfer of amino acids, glucose, and oxygen to the fetus. This decrease was accompanied by a robust reduction in maternal placental lactogen (CSH) concentrations, which we have previously demonstrated results in lower uterine blood flow and placental nutrient delivery in an in vivo model of placental CSH RNAi in sheep. Thus, we hypothesize that fetal glucagon regulates placental nutrient delivery by inhibiting placental trophoblast CSH secretion and uterine blood flow. This proposal will demonstrate that fetal glucagon acts by matching placental nutrient delivery to fetal growth and metabolic demands by regulating maternal CSH secretion and NO-mediated vasodilation to alter blood flow. Aim 1 will establish the mechanism by which fetal glucagon inhibits CSH secretion by the trophoblast. Aim 2 will identify the link between fetal glucagon, CSH, and uterine blood flow, and how this relationship regulates vasoactivity and placental nutrient delivery. Expected outcomes: This proposal will be the first mechanistic physiological investigation into fetal glucagon as an inhibitor of trophoblast CSH production, regulating uterine blood flow and placental nutrient transfer. Furthermore, it will also demonstrate the novel vasodilatory role of CSH in uterine circulation. Lastly, this proposal will provide me critical training in fetal physiology, improve the translatability of my research by working with human samples, augment my grantsmanship and scientific writing skills, and cultivate key professional relationships to establish successful future collaborations as a tenure-track, assistant professor specializing in fetal-placental-maternal communication. Impact: The research outlined by this proposal will identify a previously unknown mechanism for matching nutrient delivery to fetal metabolic demand to increase survival during pregnancy complications.