{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:49:03Z","timestamp":1787064543961,"version":"build-2736575974"},"reference-count":28,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Fetal growth restriction is linked to placental oxidative stress owing to defective placentation and hypoxia\u2013reoxygenation (H\/R). Angiotensin\u2010converting enzyme 2 (ACE2), a key regulator of oxidative stress, is reduced in placentae of fetuses with growth restriction. We aimed to develop a physiologically relevant model of repeated H\/R to determine the protective role of ACE2 during repeated H\/R insult. Human term placental explants (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a08 per group) were cultured for 24\u00a0h in normoxia (8% O\n                      <jats:sub>2<\/jats:sub>\n                      ), non\u2010physiological H\/R [6\u00a0h cycles of 1% (hypoxia chamber) and 8% O\n                      <jats:sub>2<\/jats:sub>\n                      (incubator)] or our novel physiological H\/R model (6\u00a0h cycles of 1% and 8% O\n                      <jats:sub>2<\/jats:sub>\n                      in a single hypoxia chamber), with or without recombinant human (rh)ACE2. Physiological H\/R, in contrast to non\u2010physiological H\/R, decreased membrane\u2010bound ACE2 protein compared with normoxia. Physiological H\/R also increased NADPH oxidase 5 (\n                      <jats:italic>NOX5<\/jats:italic>\n                      ) mRNA and protein, NOX4 protein and xanthine dehydrogenase (\n                      <jats:italic>XDH<\/jats:italic>\n                      ) mRNA compared with normoxia. Physiological H\/R increased levels of antioxidants superoxide dismutase 1 (\n                      <jats:italic>SOD1<\/jats:italic>\n                      ) mRNA, heme oxygenase 1 (\n                      <jats:italic>HO\u20101<\/jats:italic>\n                      ) mRNA and protein, and glutathione reductase (\n                      <jats:italic>GSR<\/jats:italic>\n                      ), nuclear factor erythroid 2\u2010related factor (\n                      <jats:italic>Nrf2<\/jats:italic>\n                      ) and NADPH quinone oxidoreductase 1 (\n                      <jats:italic>NQO1<\/jats:italic>\n                      ) mRNA above normoxia. Conversely, physiological H\/R reduced SOD, CAT and GPx activity below normoxia. Non\u2010physiological H\/R had no effect on ROS or antioxidant enzymes except for increasing\n                      <jats:italic>GSR<\/jats:italic>\n                      mRNA compared with normoxia. The rhACE2 reduced\n                      <jats:italic>NOX5<\/jats:italic>\n                      \u00a0mRNA and NOX4 and NOX5 protein and increased CAT and GPx activities compared with physiological H\/R alone. Using a novel repeated H\/R model, we show that repeated H\/R downregulates ACE2 protein and induces placental oxidative stress, which can be mitigated by rhACE2\n                      <jats:italic>in vitro<\/jats:italic>\n                      .\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70187-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>A physiologically relevant repeated hypoxia\u2013reoxygenation (H\/R) model was established using human placental explants that show upregulated NOX5, NOX4 and XDH, driving the generation of reactive oxygen species.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Repeated H\/R insult reduces membrane\u2010bound ACE2 protein, contributing to oxidative stress in placental tissue.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The mRNA and protein levels of key antioxidants (SOD1, HO\u20101, GSR, Nrf2 and NQO1) were elevated, but paradoxically, enzymatic activities (SOD, CAT and GPx) were reduced.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Recombinant human ACE2\u00a0supplementation reversed oxidative markers and restored antioxidant enzyme activities, thereby mitigating H\/R\u2010induced placental dysfunction.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Our findings enhance understanding of placental oxidative regulation and offer new therapeutic direction for fetal growth restriction.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp289678","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T19:45:31Z","timestamp":1760643931000},"page":"7305-7321","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Angiotensin\u2010converting enzyme 2 regulates the placental response to repeated hypoxia\u2013reoxygenation insult"],"prefix":"10.1113","volume":"603","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0245-9582","authenticated-orcid":false,"given":"India A.","family":"Brooker","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing University of Newcastle Callaghan (Awabakal Country) NSW Australia"},{"name":"Women's Health Research Program Hunter Medical Research Institute New Lambton Heights (Awabakal Country) NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9672-2371","authenticated-orcid":false,"given":"Jessie M.","family":"Sutherland","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing University of Newcastle Callaghan (Awabakal Country) NSW Australia"},{"name":"Women's Health Research Program Hunter Medical Research Institute New Lambton Heights (Awabakal Country) NSW 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