{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T04:27:40Z","timestamp":1793161660757,"version":"4.5.0"},"reference-count":76,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP 23K05601"],"award-info":[{"award-number":["JP 23K05601"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Physiological hypoxia is a defining feature of early pregnancy, coordinating menstrual repair, implantation, decidualization, placental development, and fetoplacental adaptation. Hypoxia-inducible factors, HIF-1\u03b1 and HIF-2\u03b1, act as master regulators of these processes by sensing oxygen tension and orchestrating cellular responses in metabolism, angiogenesis, immune regulation, and tissue remodeling. Although structurally related, HIF-1\u03b1 and HIF-2\u03b1 exhibit distinct spatial and temporal functions across reproductive stages. Embryonic HIF-1\u03b1 is primarily involved in early embryonic development, whereas embryonic HIF-2\u03b1 is required for later developmental stages. Furthermore, maternal HIF-1\u03b1 acts early in pregnancy, coordinating metabolic adaptation, endometrial regeneration, decidualization, angiogenic expansion, placental organization, and maternal immune tolerance. In contrast, maternal HIF-2\u03b1 regulates epithelial breakdown, trophoblast invasion, implantation mechanics, and vesicle-mediated trafficking. Mouse genetics demonstrate that disruption of either isoform leads to non-redundant defects in reproductive success, from failed implantation to placental insufficiency and fetal lethality. Pathological hypoxia or aberrant HIF signaling drives pregnancy disorders including preeclampsia, fetal growth restriction, recurrent pregnancy loss, and heavy menstrual bleeding. Defining the distinct roles of HIF-1\u03b1 and HIF-2\u03b1 supports the development of therapies targeting hypoxia-responsive pathways in infertility and obstetric disease.<\/jats:p>","DOI":"10.3390\/ijms27031593","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T10:05:47Z","timestamp":1770372347000},"page":"1593","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Divergent Roles of HIF-1\u03b1 and HIF-2\u03b1 in Embryonic Development and Early Pregnancy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1962-9701","authenticated-orcid":false,"given":"Hossam H.","family":"Shawki","sequence":"first","affiliation":[{"name":"Department of Comparative and Experimental Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan"},{"name":"National Gene Bank of Egypt, ARC, Giza 12619, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4405-4705","authenticated-orcid":false,"given":"Asmaa Y.","family":"Ammar","sequence":"additional","affiliation":[{"name":"Biotechnology Department, Animal Health Research Institute, ARC, Giza 12619, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7487-8295","authenticated-orcid":false,"given":"Mohamed","family":"Mansour","sequence":"additional","affiliation":[{"name":"National Gene Bank of Egypt, ARC, Giza 12619, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma M.","family":"Minisy","sequence":"additional","affiliation":[{"name":"Department of Pathology, National Research Centre, Cairo 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/s41467-017-02375-6","article-title":"Hypoxia and Hypoxia Inducible Factor-1\u03b1 Are Required for Normal Endometrial Repair during Menstruation","volume":"9","author":"Maybin","year":"2018","journal-title":"Nat. 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