Regulation of angiogenesis at the maternal-fetal interface

胚泡着床、胎盘和成功妊娠需要着床部位母胎双方血管发育/重塑和功能适应的协调。在着床时，血管丰富的子宫内膜是成功着床的关键。着床后不久，这种血管系统的生长对促进营养和氧气向母体的运输至关重要。免疫细胞，特别是自然杀伤细胞、树突状细胞和巨噬细胞被募集到植入部位，它们在血管生成和母胎串扰调节中起着关键作用，但它们的募集信号尚不清楚。血管生成和免疫细胞功能的改变导致胎儿丢失。我们假设免疫细胞是通过特定的趋化因子信号在母胎界面募集和定位的，它们的血管生成特性是由特定的microrna调节的。利用我们先前建立的激光捕获显微解剖技术方法对猪和小鼠进行研究，Aim1将表征来自母体和胎儿侧的趋化因子募集信号（它们的合适受体/诱饵受体）。Aim2将描述免疫细胞亚群中重要的血管生成因子和调节妊娠成功的细胞因子。Aim3将定义调节血管生成和免疫细胞发育的特异性microrna。在小鼠中使用靶向锁定核酸探针，将阻断aim#3中鉴定的特异性microrna，并在Aim4中评估妊娠期间的体内效应。拟议的研究将在怀孕的特定时间点进行，以捕获子宫内膜免疫细胞的富集和血管生成的开始（猪妊娠期（gd） 15和20，小鼠妊娠期（gd） 8、10和12）。这些研究将为非侵袭性上皮性胎盘（猪）和侵袭性血流性胎盘（小鼠）的免疫细胞募集途径及其在血管生成调节和最终胎儿存活中的作用提供新的见解。这项研究的结果将有助于靶向免疫细胞及其产品减少猪的胎儿损失。拟议的研究将为2名研究生和3名暑期学生提供培训。

Blastocyst implantation, placentation and successful pregnancy require coordinated vascular development/ remodeling and functional adaptations on both maternal-fetal sides of implantation sites. At implantation, a richly vascularized endometrium is critical for successful implantation. Shortly after implantation, growth of this vasculature is essential to facilitate nutrients and oxygen transport to the conceptus. Immune cells, in particular natural killer cells, dendritic cells and macrophages are recruited to the implantation sites where they have pivotal roles in angiogenesis and regulation of maternal-fetal cross talk but their recruitment signals are poorly understood. Alterations in angiogenesis and immune cell functions lead to fetal loss. We hypothesize that immune cells are recruited and positioned within the maternal-fetal interface by specific chemokine signals and their angiogenic properties are regulated by specific microRNAs. Using our previously established technical approach of Laser Capture Microdissection for studies in pig and mice, Aim1 will characterize chemokine recruitment signals from maternal and fetal sides (their suitable receptors/decoy receptors) for immune cells. Aim2 will characterize important angiogenic factors and cytokines regulating pregnancy success in immune cell-subsets. Aim3 will define specific MicroRNAs regulating angiogenesis and immune cell development. Using targeted locked nucleic acid probes in mice, specific microRNAs identified in aim#3 will be blocked and in-vivo effects during pregnancy will be evaluated in Aim4. Proposed study will be conducted at specific time points in pregnancy to capture endometrial enrichment of immune cells and initiation of angiogenesis (gestation day (gd) 15 and 20 in porcine pregnancy and gd8, 10, 12 in mice). These studies will provide novel insights into pathways of immune cell recruitment and their role in angiogenesis regulation and ultimately fetal survival in species with non-invasive epitheliochorial placenta (pig) and invasive hemochorial placenta (mice). Outcomes from this study will help to target immune cells and their products for reducing fetal loss in pigs. Proposed research will provide training for 2 graduate and 3 summer students.