{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T03:52:07Z","timestamp":1791863527617,"version":"4.3.4"},"reference-count":85,"publisher":"American Society for Clinical Investigation","issue":"23","license":[{"start":{"date-parts":[[2022,12,8]],"date-time":"2022-12-08T00:00:00Z","timestamp":1670457600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes for Health Research","doi-asserted-by":"crossref","award":["MOP-133436"],"award-info":[{"award-number":["MOP-133436"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes for Health Research","doi-asserted-by":"crossref","award":["PJT-166090"],"award-info":[{"award-number":["PJT-166090"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000038","name":"NSERC","doi-asserted-by":"crossref","award":["RGPIN-2015-03906"],"award-info":[{"award-number":["RGPIN-2015-03906"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,8]]},"abstract":"<jats:p>\n                    Preeclampsia is a serious pregnancy disorder that lacks effective treatments other than delivery. Improper sensing of oxygen changes during placentation by prolyl hydroxylases (PHDs), specifically PHD2, causes placental hypoxia-inducible factor-1 (HIF1) buildup and abnormal downstream signaling in early-onset preeclampsia, yet therapeutic targeting of HIF1 has never been attempted. Here we generated a conditional (placenta-specific) knockout of\n                    <jats:italic>Phd2<\/jats:italic>\n                    in mice (\n                    <jats:italic>\n                      Phd2\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    cKO) to reproduce HIF1 excess and to assess anti-HIF therapy. Conditional deletion of\n                    <jats:italic>Phd2<\/jats:italic>\n                    in the junctional zone during pregnancy increased placental HIF1 content, resulting in abnormal placentation, impaired remodeling of the uterine spiral arteries, and fetal growth restriction. Pregnant dams developed new-onset hypertension at midgestation (E9.5) in addition to proteinuria and renal and cardiac pathology, hallmarks of severe preeclampsia in humans. Daily injection of acriflavine, a small molecule inhibitor of HIF1, to pregnant\n                    <jats:italic>\n                      Phd2\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    cKO mice from E7.5 (prior to hypertension) or E10.5 (after hypertension had been established) to E14.5 corrected placental dysmorphologies and improved fetal growth. Moreover, it reduced maternal blood pressure and reverted renal and myocardial pathology. Thus, therapeutic targeting of the HIF pathway may improve placental development and function, as well as maternal and fetal health, in preeclampsia.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.158908","type":"journal-article","created":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T12:00:34Z","timestamp":1665662434000},"source":"Crossref","is-referenced-by-count":26,"title":["HIF1 inhibitor acriflavine rescues early-onset preeclampsia phenotype in mice lacking placental prolyl hydroxylase domain protein 2"],"prefix":"10.1172","volume":"7","author":[{"given":"Julien","family":"Sallais","sequence":"first","affiliation":[{"name":"Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada."},{"name":"Institute of Medical Sciences, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanho","family":"Park","sequence":"additional","affiliation":[{"name":"Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada."},{"name":"Department of Physiology, University of Toronto, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sruthi","family":"Alahari","sequence":"additional","affiliation":[{"name":"Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada."},{"name":"Department of Physiology, University of Toronto, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Porter","sequence":"additional","affiliation":[{"name":"Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5342-7118","authenticated-orcid":true,"given":"Ruizhe","family":"Liu","sequence":"additional","affiliation":[{"name":"Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada."},{"name":"Department of Physiology, University of Toronto, Ontario, 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