Integrating Environmental Cues at the Maternal-Fetal Vascular Interface

2.总结 大多数有指征的早产是由于缺血性胎盘疾病如先兆子痫（PE）和 宫内生长受限（IUGR）（1-4）。在这些条件下，母胎界面的特征在于： 一组胎盘发现统称为母体血管灌注不良（MVM）（5-7）。这通常 涉及母体螺旋小动脉的侵袭和重塑受损，导致胎盘 灌注（5，6，8-17），和/或受损的绒毛发育，损害建立有效的 母胎运输界面（5，6，18，19）。我们和其他人已经表明，环境因素， 氧分压可以调节胎盘发育并促进缺血性胎盘疾病过程 通过调节缺氧诱导因子（HIF）依赖性基因表达（10，20-31）。无与伦比的 研究环境对胚胎和胎盘发育的影响的机会出现在体外 受精（IVF）。我们已经证明，IVF对囊胚基因表达、细胞数量、 着床潜力、胎盘发育、胚胎和胎盘生长速度以及成人健康 （32-42）。重要的是，多项基于人口的研究现在证实，环境操纵 与IVF相关的高血压显著增加了人类PE和IUGR的风险（RR 2.5倍）（43-49）。这里我们 证实了这些发现，并表明母胎转运界面的发育是特异性的， 在小鼠和人类体外受精后受损，并提供证据表明HIF信号的改变可能起作用。 支持这一点的是，我们证明了在小鼠IVF受孕中，HIF-2α mRNA增加，但活性降低， 可能是由于氧化还原应激和受损的线粒体生物能量学，沿着随后的缺陷， 滋养层分化和胎盘的发育。我们进一步表明，HIF-2α连接 滋养层细胞的代谢和分化方式与HIF-1α显著不同，并假设 胎盘内的代谢重编程，加上受损的转运蛋白基因表达， 母胎运输界面的发展，导致胎儿生长受限和PE风险， 设置.与此一致，我们发现人类妊娠的IVF状态与绒毛受损有关。 损害母胎转运界面的发育，降低HIF-2α和Glut-3表达， PE风险增加。基于这些观察结果，我们建议进一步定义HIF-1α和HIF-2 α依赖性 对滋养层分化、功能和代谢的影响，以及它们如何受到啮齿动物IVF状态的影响 模型，以及它们在人类缺血性胎盘疾病发病机制中的作用程度 通过IVF怀孕。调查人员的集体专业知识使我们能够 推进我们对缺血性胎盘的环境驱动因素和代谢后果的理解， 疾病过程，ART方法如何与它们协同作用，并确定新的干预目标。

2. SUMMARY Most indicated preterm deliveries occur due to ischemic placental diseases such as preeclampsia (PE) and intrauterine growth restriction (IUGR) (1-4). The maternal-fetal interface in these conditions is characterized by a set of placental findings collectively referred to as maternal vascular malperfusion (MVM) (5-7). This typically involves either impaired invasion and remodeling of maternal spiral arterioles, resulting in diminished placental perfusion (5, 6, 8-17), and/or impaired villous development, compromising establishment of an efficient maternal-fetal transport interface (5, 6, 18, 19). We and others have shown that environmental factors such as oxygen tension can modulate placental development and contribute to ischemic placental disease processes via modulation of Hypoxia-inducible Factor (HIF)-dependent gene expression (10, 20-31). An unparalleled opportunity to study environmental effects on embryonic and placental development occurs during in vitro fertilization (IVF). We have shown that IVF has significant effects on blastocyst gene expression, cell number, potential for implantation, placental development, embryonic and placental growth velocity, and adult health (32-42). Importantly, multiple large population-based studies now confirm that environmental manipulation associated with IVF significantly increases PE risk and IUGR in humans (RR 2.5 fold) (43-49). Here, we confirm these findings and demonstrate that development of the maternal-fetal transport interface is specifically impaired following IVF in mice and humans, and provide evidence that altered HIF signaling may play a role. Supporting this, we demonstrate increased Hif-2α mRNA but decreased activity in murine IVF conceptuses, likely due to redox stress and impaired mitochondrial bioenergetics, along with subsequent defects in trophoblast differentiation and development of the labyrinthine placenta. We further show that HIF-2α links trophoblast metabolism and differentiation in ways that differ significantly from HIF-1α, and postulate that metabolic reprogramming within the placenta, coupled with impaired transporter gene expression and development of the maternal-fetal transport interface, contribute to fetal growth restriction and PE risk in this setting. Consistent with this, we find that IVF status in human pregnancies is associated with impaired villous development compromising the maternal-fetal transport interface, decreased HIF-2α and Glut-3 expression, and increased PE risk. Based on these observations, we propose to further define HIF-1α and -2α dependent effects on trophoblast differentiation, function and metabolism, how they are impacted by IVF status in rodent models, and the extent to which they contribute to the pathogenesis of ischemic placental diseases in human pregnancies conceived by IVF. The collective expertise of the investigators involved uniquely positions us to advance our understanding of the environmental drivers and metabolic consequences of ischemic placental disease processes, how ART methodologies synergize with them, and to identify novel targets for intervention.