{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:04:40Z","timestamp":1791331480183,"version":"4.3.1"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T00:00:00Z","timestamp":1634601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science KAKENHI","doi-asserted-by":"crossref","award":["JP20K09675"],"award-info":[{"award-number":["JP20K09675"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Placental hypoxia and increased levels of maternal blood anti-angiogenic protein, soluble fms-like tyrosine kinase-1 (sFLT1), are associated with the pathogenesis of pre-eclampsia. We have demonstrated that hypoxia-inducible factor (HIF)-2\u03b1 mediates the upregulation of the hypoxia-induced FLT1 gene in trophoblasts and their cell lines. Here, we investigated the involvement of HIF-1\u03b2, which acts as a dimerization partner for HIF-\u03b1, in the upregulation of the FLT1 gene via hypoxia. We confirmed the interactions between HIF-1\u03b2 and HIF-2\u03b1 in the nuclei of BeWo, JAR and JEG-3 cells under hypoxia via co-immunoprecipitation. We found that hypoxia-induced upregulation of the FLT1 gene in BeWo cells and secretion of sFLT1 in human primary trophoblasts were significantly reduced by siRNAs targeting HIF-1\u03b2. Moreover, the upregulation of the FLT1 gene in BeWo cells induced by dimethyloxaloylglycine (DMOG) was also inhibited by silencing either HIF-2\u03b1 or HIF-1\u03b2 mRNA. It was recently shown that DNA demethylation increases both basal and hypoxia-induced expression levels of the FLT1 gene in three trophoblast-derived cell lines. In the demethylated BeWo cells, siRNAs targeting HIF-2\u03b1 and HIF-1\u03b2 suppressed the further increase in the expression levels of the FLT1 gene due to hypoxia or treatment with DMOG. However, luciferase reporter assays and bisulfite sequencing revealed that a hypoxia response element (\u2212966 to \u2212962) of the FLT1 gene is not involved in hypoxia or DMOG-induced upregulation of the FLT1 gene. These findings suggest that HIF-1\u03b2 is essential for the elevated production of sFLT1 in the hypoxic trophoblasts and that the HIF-2\u03b1\/HIF-1\u03b2 complex may be a crucial therapeutic target for pre-eclampsia.<\/jats:p>","DOI":"10.1093\/molehr\/gaab065","type":"journal-article","created":{"date-parts":[[2021,10,16]],"date-time":"2021-10-16T04:15:23Z","timestamp":1634357723000},"source":"Crossref","is-referenced-by-count":24,"title":["Hypoxia-inducible factor-1\u03b2 is essential for upregulation of the hypoxia-induced <i>FLT1<\/i> gene in placental trophoblasts"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4241-3260","authenticated-orcid":false,"given":"Tadashi","family":"Sasagawa","sequence":"first","affiliation":[{"name":"Institute of Physiology and Medicine, Jobu University, Gunma 370-1393, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Nagamatsu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manami","family":"Yanagisawa","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8277-8400","authenticated-orcid":false,"given":"Masabumi","family":"Shibuya","sequence":"additional","affiliation":[{"name":"Institute of Physiology and Medicine, Jobu University, Gunma 370-1393, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,10,19]]},"reference":[{"key":"2021120108245695700_gaab065-B1","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1007\/s004240100679","article-title":"Attenuation of HIF-1 DNA-binding activity limits hypoxia-inducible endothelin-1 expression","volume":"443","author":"Camenisch","year":"2001","journal-title":"Pflugers Arch Eur Arch"},{"key":"2021120108245695700_gaab065-B2","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1038\/s41591-021-01324-7","article-title":"Inhibition of hypoxia-inducible factor-2\u03b1 in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis","volume":"27","author":"Choueiri","year":"2021","journal-title":"Nat Med"},{"key":"2021120108245695700_gaab065-B3","doi-asserted-by":"crossref","first-page":"15222","DOI":"10.1096\/fj.202001681R","article-title":"Hypoxia-inducible factor 2 alpha impairs human cytotrophoblast syncytialization: new insights into placental dysfunction and fetal growth restriction","volume":"34","author":"Colson","year":"2020","journal-title":"FASEB J"},{"key":"2021120108245695700_gaab065-B4","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1200\/JCO.2017.74.2627","article-title":"Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2\u03b1 antagonist in patients with previously treated advanced clear cell renal cell carcinoma","volume":"36","author":"Courtney","year":"2018","journal-title":"J Clin Oncol"},{"key":"2021120108245695700_gaab065-B5","doi-asserted-by":"crossref","first-page":"4370","DOI":"10.3390\/ijms20184370","article-title":"Molecular targets of aspirin and prevention of preeclampsia and their potential association with circulating extracellular vesicles during pregnancy","volume":"20","author":"Dutta","year":"2019","journal-title":"Int J Mol Sci"},{"key":"2021120108245695700_gaab065-B6","doi-asserted-by":"crossref","first-page":"12455","DOI":"10.1038\/s41598-017-12685-w","article-title":"Enhanced HIF2\u03b1 expression during human trophoblast differentiation into syncytiotrophoblast suppresses transcription of placental growth factor","volume":"7","author":"Fujii","year":"2017","journal-title":"Sci Rep"},{"key":"2021120108245695700_gaab065-B7","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.placenta.2005.09.001","article-title":"Designing pregnancy centered medications: drugs which do not cross the human placenta","volume":"27","author":"Gedeon","year":"2006","journal-title":"Placenta"},{"key":"2021120108245695700_gaab065-B8","doi-asserted-by":"crossref","first-page":"23659","DOI":"10.1074\/jbc.272.38.23659","article-title":"Differential transcriptional regulation of the two vascular endothelialgrowth factor receptor genes. 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