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Barry E Perlman, Audrey A Merriam, Alexander Lemenze, Qingshi Zhao, Salma Begum, Mohan Nair, Tracy Wu, Ronald J Wapner, Jan K Kitajewski, Carrie J Shawber, and Nataki C. Douglas

In the 1st trimester of human pregnancy, low oxygen tension or hypoxia, is essential for proper placentation and placenta function. Low oxygen levels and activation of signaling pathways have been implicated as critical mediators in the promotion of trophoblast differentiation, migration, and invasion with inappropriate changes in oxygen tension and aberrant Notch signaling both individually reported as causative to abnormal placentation. Despite crosstalk between hypoxia and Notch signaling in multuple cell types, the relationship between hypoxia and Notch in 1st trimester trophoblast function is not understood. To determine how a low oxygen environment impacts Notch signaling and cellular motility, we utilized the human 1st trimester trophoblast cell line, HTR-8/SVneo. Gene set enrichment and ontology analyses identified pathways involved in angiogenesis, Notch and cellular migration as upregulated in HTR-8/SVneo cells exposed to hypoxic conditions. DAPT, a -secretase inhibitor that inhibits Notch activation, was used to interrogate the crosstalk between Notch and hypoxia pathways in HTR-8/SVneo cells. We found that hypoxia requires Notch activation to mediate HTR-8/SVneo cell migration, but not invasion. To determine if our in vitro findings were associated with preeclampsia, we analyzed 2nd trimester chorionic villous sampling (CVS) samples and 3rd trimester placentas. We found a significant decrease in expression of migration and invasion genes in CVS from preeclamptic pregnancies, and significantly lower levels of JAG1 in placentas from pregnancies with early-onset preeclampsia with severe features. Our data support a role for Notch in mediating hypoxia-induced trophoblast migration, which may contribute to preeclampsia development.