{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T20:38:45Z","timestamp":1791837525240,"version":"4.3.4"},"reference-count":52,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,3,2]],"date-time":"2022-03-02T00:00:00Z","timestamp":1646179200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP571329, APP1066606"],"award-info":[{"award-number":["APP571329, APP1066606"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009021","name":"Heart Research Australia","doi-asserted-by":"publisher","award":["APP2014-01"],"award-info":[{"award-number":["APP2014-01"]}],"id":[{"id":"10.13039\/100009021","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011522","name":"SOMANZ","doi-asserted-by":"publisher","award":["APP2015-KP"],"award-info":[{"award-number":["APP2015-KP"]}],"id":[{"id":"10.13039\/100011522","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Preeclampsia (PE) and intrauterine growth restriction (IUGR) are the leading causes of maternal and fetal morbidity\/mortality. The central deficit in both conditions is impaired placentation due to poor trophoblast invasion, resulting in a hypoxic milieu in which oxidative stress contributes to the pathology. We examine the factors driving the hypoxic response in severely preterm PE (n = 19) and IUGR (n = 16) placentae compared to the spontaneous preterm (SPT) controls (n = 13) using immunoblotting, RT-PCR, immunohistochemistry, proximity ligation assays, and Co-IP. Both hypoxia-inducible factor (HIF)-1\u03b1 and HIF-2\u03b1 are increased at the protein level and functional in pathological placentae, as target genes prolyl hydroxylase domain (PHD)2, PHD3, and soluble fms-like tyrosine kinase-1 (sFlt-1) are increased. Accumulation of HIF-\u03b1-subunits occurs in the presence of accessory molecules required for their degradation (PHD1, PHD2, and PHD3 and the E3 ligase von Hippel\u2013Lindau (VHL)), which were equally expressed or elevated in the placental lysates of PE and IUGR. However, complex formation between VHL and HIF-\u03b1-subunits is defective. This is associated with enhanced VHL\/DJ1 complex formation in both PE and IUGR. In conclusion, we establish a significant mechanism driving the maladaptive responses to hypoxia in the placentae from severe PE and IUGR, which is central to the pathogenesis of both diseases.<\/jats:p>","DOI":"10.3390\/ijms23052772","type":"journal-article","created":{"date-parts":[[2022,3,2]],"date-time":"2022-03-02T08:37:16Z","timestamp":1646210236000},"page":"2772","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Dysregulation of Oxygen Sensing\/Response Pathways in Pregnancies Complicated by Idiopathic Intrauterine Growth Restriction and Early-Onset Preeclampsia"],"prefix":"10.3390","volume":"23","author":[{"given":"Sharon A.","family":"McCracken","sequence":"first","affiliation":[{"name":"Division of Perinatal Medicine, Faculty of Medicine and Health, The University of Sydney, Northern Sydney Local Health District Research (Kolling Institute), St. Leonards, NSW 2065, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean K. M.","family":"Seeho","sequence":"additional","affiliation":[{"name":"Division of Perinatal Medicine, Faculty of Medicine and Health, The University of Sydney, Northern Sydney Local Health District Research (Kolling Institute), St. Leonards, NSW 2065, Australia"},{"name":"Department of Obstetrics and Gynaecology, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Carrodus","sequence":"additional","affiliation":[{"name":"Division of Perinatal Medicine, Faculty of Medicine and Health, The University of Sydney, Northern Sydney Local Health District Research (Kolling Institute), St. Leonards, NSW 2065, Australia"},{"name":"School of Biomedical Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny H.","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Perinatal Medicine, Faculty of Medicine and Health, The University of Sydney, Northern Sydney Local Health District Research (Kolling Institute), St. Leonards, NSW 2065, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narelle","family":"Woodland","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileen D. M.","family":"Gallery","sequence":"additional","affiliation":[{"name":"Division of Perinatal Medicine, Faculty of Medicine and Health, The University of Sydney, Northern Sydney Local Health District Research (Kolling Institute), St. Leonards, NSW 2065, Australia"},{"name":"Department of Obstetrics and Gynaecology, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Morris","sequence":"additional","affiliation":[{"name":"Division of Perinatal Medicine, Faculty of Medicine and Health, The University of Sydney, Northern Sydney Local Health District Research (Kolling Institute), St. Leonards, NSW 2065, Australia"},{"name":"Department of Obstetrics and Gynaecology, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony W.","family":"Ashton","sequence":"additional","affiliation":[{"name":"Division of Perinatal Medicine, Faculty of Medicine and Health, The University of Sydney, Northern Sydney Local Health District Research (Kolling Institute), St. Leonards, NSW 2065, Australia"},{"name":"Department of Obstetrics and Gynaecology, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1097\/00003081-200606000-00009","article-title":"Adult consequences of fetal growth restriction","volume":"49","author":"Barker","year":"2006","journal-title":"Clin. 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