Fetal glucagon links fetal metabolism with uterine blood flow and placental nutrient transfer by inhibiting placental lactogen secretion

项目摘要 我们的目标是建立一个新的框架，了解胎儿生长的调节。为此， 我们将证明胎儿胰高血糖素和母体胎盘催乳素的新作用。现行教条 认为母亲的营养和激素状况，子宫血流，以及早期事件， 胎盘发育调节胎盘营养输送和胎儿生长。然而，知识 这种认识上的差距阻碍了成功治疗胎儿疾病的进展。 妊娠并发症期间的生长。这项建议将显示胎儿胰高血糖素如何抑制子宫内膜 通过抑制胎盘催乳素分泌到 母体循环我们最近证明，实验性增加胎儿胰高血糖素， 将胎儿胰高血糖素直接输注到妊娠晚期胎羊中的浓度降低了子宫血， 胎盘从母体循环中摄取营养和氧气，胎盘输送氨基 胎儿血浆氨基酸浓度、胎儿血浆氨基酸浓度、胎儿血浆 合成代谢生长因子胰岛素和IGF-1，以及胎儿蛋白质增加。这些都与一个 在九天的输液后胎儿体重减少了13%。此外，我们已经证明， 在怀孕绵羊中实验性地降低胎盘催乳素导致子宫血流量降低， 胎盘营养物质的输送与其在调节母体营养物质中的经典作用无关 新陈代谢.我们已经反复证明，增加胎儿氨基酸提高胎儿胰高血糖素 浓度的总之，这些数据支持我们的总体假设：胎儿胰高血糖素 通过抑制PL分泌使胎盘营养输送与胎儿代谢需求相匹配。这 将在妊娠绵羊、分离的人原代滋养层细胞和子宫和 分别从妊娠绵羊和人分离的子宫肌层动脉。在目标#1中，我们将展示 胎儿胰高血糖素抑制胎儿生长的机制是通过降低胎盘氨基酸 分娩和胎儿氨基酸浓度。在目标#2中，我们将通过以下方式证明该机制： 胎儿胰高血糖素抑制子宫血流和胎盘营养输送是通过降低胎盘 催乳素分泌在目标3中，我们将建立胰高血糖素抑制胎盘生长的机制。 催乳素分泌这一建议将是第一个机制的生理调查胎儿 胰高血糖素作为子宫血流、胎盘营养输送和胎儿生长的抑制剂， 胎盘催乳素在子宫循环中作为血管扩张剂。其影响将是改变范式 对我们了解胎儿生长的调节有很大帮助。如果我们要制作新的，这是必需的 妊娠合并胎盘早剥胎儿生长障碍的处理进展 营养不足、先兆子痫、糖尿病、母体肥胖和其它病症。

PROJECT ABSTRACT Our goal is to establish a new framework for understanding the regulation of fetal growth. To do so, we will demonstrate novel roles for fetal glucagon and maternal placental lactogen. Current dogma holds that the mother's nutritional and hormonal status, uterine blood flow, and early events in placental development regulate placental nutrient delivery and fetal growth. However, knowledge gaps in this understanding have prevented progress towards successful treatment of disordered fetal growth during complications of pregnancy. This proposal will show how fetal glucagon inhibits uterine blood flow and placental nutrient delivery by inhibiting secretion of placental lactogen into the maternal circulation. We have recently demonstrated that experimentally increasing fetal glucagon concentrations with direct fetal glucagon infusions into late gestation fetal sheep lowers uterine blood, placental uptake of nutrients and oxygen from the maternal circulation, placental delivery of amino acids to the fetus, fetal plasma concentrations of amino acids, fetal plasma concentrations of the anabolic growth factors insulin and IGF-1, and fetal protein accretion. These were associated with a 13% reduction in fetal weight after just a nine-day infusion. Additionally, we have demonstrated that experimentally lowering placental lactogen in pregnant sheep results in lower uterine blood flow and placental nutrient delivery independent of its classically described role in regulating maternal nutrient metabolism. We have repeatedly shown that increasing fetal amino acids raises fetal glucagon concentrations. Taken together, these data support our overarching hypothesis: fetal glucagon matches placental nutrient delivery to fetal metabolic demand by inhibiting PL secretion. This hypothesis will be tested in pregnant sheep, isolated human primary trophoblasts, and uterine and myometrial arteries isolated from pregnant sheep and humans, respectively. In Aim #1 we will show that the mechanism by which fetal glucagon inhibits fetal growth is by lowering placental amino acid delivery and fetal amino acid concentrations. In Aim #2 we will demonstrate that the mechanism by which fetal glucagon inhibits uterine blood flow and placental nutrient delivery is by lowering placental lactogen secretion. In Aim #3 we will establish the mechanism by which glucagon inhibits placental lactogen secretion. This proposal will be the first mechanistic physiological investigation into fetal glucagon as an inhibitor of uterine blood flow, placental nutrient delivery, and fetal growth and placental lactogen as a vasodilator in the uterine circulation. The impact will be to shift the paradigm for our understanding of the regulation of fetal growth. This is required if we are to make new advances into the management of disordered fetal growth in pregnancies complicated by placental insufficiency, preeclampsia, diabetes, maternal obesity and other conditions.