Regulation of angiogenesis at the maternal-fetal interface

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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.