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This study aimed to characterize endothelial protein C receptor (EPCR) in preterm preeclampsia, term preeclampsia, and fetal growth restriction (defined by delivery of a small for gestational age [SGA] infant [&lt;10% birthweight centile]) and examine its regulation in primary syncytiotrophoblast. Placental EPCR mRNA and protein were significantly increased in patients with preterm preeclampsia (&lt;34\u2009weeks gestation) compared to gestation\u2010matched controls (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u2009.0001). In the plasma, EPCR was also significantly elevated (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a0.01) in established preterm preeclampsia while its substrate, protein C (PC) was significantly reduced (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a0.0083). Placentas from preterm small for gestational age (SGA) cases, had elevated EPCR mRNA expression (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u2009.0001) relative to controls. At 36\u2009weeks, no significant changes in plasma EPCR were detected in samples from patients destined to develop preeclampsia or deliver an SGA infant at term. In terms of syncytiotrophoblast, hypoxia significantly increased EPCR mRNA expression (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a0.008), but Tumor Necrosis Factor Alpha (TNF\u2010\u03b1) decreased EPCR mRNA. Interleukin\u20106 (IL\u20106) had no significant effect on EPCR mRNA expression. When isolated syncytiotrophoblast was treated with metformin under hypoxia (1% O\n                    <jats:sub>2<\/jats:sub>\n                    ) or normoxia (8% O\n                    <jats:sub>2<\/jats:sub>\n                    ), EPCR mRNA expression was significantly reduced (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a0.008) relative to control. In conclusion, EPCR is markedly elevated in the placenta and the circulation of patients with established preterm preeclampsia and placental increases may be associated with hypoxia. Additionally, fetal growth\u2010restricted pregnancies (as defined by the delivery of an SGA infant) also demonstrated elevated placental EPCR.\n                  <\/jats:p>","DOI":"10.1096\/fj.202201150r","type":"journal-article","created":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T10:12:24Z","timestamp":1668679944000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Endothelial protein C receptor is increased in preterm preeclampsia and fetal growth restriction"],"prefix":"10.1096","volume":"36","author":[{"given":"Faith","family":"Andres","sequence":"first","affiliation":[{"name":"Translational Obstetrics Group, Department of Obstetrics and Gynaecology Mercy Hospital for Women, The University of Melbourne  Heidelberg Victoria Australia"},{"name":"Mercy Perinatal, Mercy Hospital for Women  Heidelberg Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalie J.","family":"Hannan","sequence":"additional","affiliation":[{"name":"Mercy Perinatal, Mercy Hospital for Women  Heidelberg Victoria Australia"},{"name":"Therapeutics Discovery and Vascular Function Group, Department of Obstetrics and Gynaecology Mercy Hospital for Women, The University of Melbourne  Heidelberg Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan P.","family":"Walker","sequence":"additional","affiliation":[{"name":"Translational Obstetrics Group, Department of Obstetrics and Gynaecology Mercy Hospital for Women, The University of Melbourne  Heidelberg Victoria Australia"},{"name":"Mercy Perinatal, Mercy Hospital for Women  Heidelberg Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa M.","family":"MacDonald","sequence":"additional","affiliation":[{"name":"Translational Obstetrics Group, Department of Obstetrics and Gynaecology Mercy Hospital for Women, The University of Melbourne  Heidelberg 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