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Highly expressed in secretory endometrium and trophectoderm cells, previous studies suggest that it may regulate implantation by orchestrating the surface expression of integrins and other membrane proteins. In order to test the role of EMP2<\/jats:styled-content> in pregnancy, mice lacking EMP2<\/jats:styled-content> (Emp2<\/jats:italic>\u2212\/\u2212<\/jats:sup>) were generated. Emp2<\/jats:italic>\u2212\/\u2212<\/jats:sup> females are fertile but have reduced litter sizes when carrying Emp2<\/jats:italic>\u2212\/\u2212<\/jats:sup> but not Emp2<\/jats:italic>+\/\u2212<\/jats:sup> fetuses. Placentas of Emp2<\/jats:italic>\u2212\/\u2212<\/jats:sup> fetuses exhibit dysregulation in pathways related to neoangiogenesis, coagulation, and oxidative stress, and have increased fibrin deposition and altered vasculature. Given that these findings often occur due to placental insufficiency resulting in an oxygen\u2010poor environment, the expression of hypoxia\u2010inducible factor\u20101 alpha (HIF<\/jats:styled-content>\u20101\u03b1) was examined. Placentas from Emp2<\/jats:italic>\u2212\/\u2212<\/jats:sup> fetuses had increased total HIF<\/jats:styled-content>\u20101\u03b1 expression in large part through an increase in uterine NK<\/jats:styled-content> (uNK<\/jats:styled-content>) cells, demonstrating a unique interplay between uNK<\/jats:styled-content> cells and trophoblasts modulated through EMP2<\/jats:styled-content>. To determine if these results translated to human pregnancy, placentas from normal, term deliveries or those complicated by placental insufficiency resulting in intrauterine growth restriction (IUGR<\/jats:styled-content>) were stained for EMP2<\/jats:styled-content>. EMP2<\/jats:styled-content> was significantly reduced in both villous and extravillous trophoblast populations in IUGR<\/jats:styled-content> placentas. Experiments in vitro<\/jats:italic> using human trophoblast cells lines indicate that EMP2<\/jats:styled-content> modulates angiogenesis by altering HIF<\/jats:styled-content>\u20101\u03b1 expression. Our results reveal a novel role for EMP2<\/jats:styled-content> in regulating trophoblast function and vascular development in mice and humans, and suggest that it may be a new biomarker for placental insufficiency. Copyright \u00a9 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4893","type":"journal-article","created":{"date-parts":[[2017,3,14]],"date-time":"2017-03-14T17:16:30Z","timestamp":1489511790000},"page":"246-259","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Epithelial membrane protein 2 (EMP2<\/scp>) deficiency alters placental angiogenesis, mimicking features of human placental insufficiency"],"prefix":"10.1002","volume":"242","author":[{"given":"Carmen J","family":"Williams","sequence":"first","affiliation":[{"name":"Reproductive Medicine Group, Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences National Institutes of Health Research Triangle Park NC 27709 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Neonatology Geffen School of 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