{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T02:45:17Z","timestamp":1789785917597,"version":"4.0.1"},"reference-count":40,"publisher":"The Endocrine Society","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>During early pregnancy, cytotrophoblast cells differentiate into extravillous trophoblast (EVT) cells and invade the uterine spiral arteries. This physiological process is essential for the development of maternal-fetal circulation. Because EVT cells are exposed to a low-oxygen environment during this process, we investigated the role of hypoxia in the mechanism that regulates the invasive behavior of EVT cells. Real-time PCR and immunofluorescent analysis were performed to investigate how hypoxia influences the expression of E-cadherin in villous explants cultures and in trophoblast-derived BeWo cells. We determined that hypoxia induced E-cadherin down-regulation through Snail up-regulation in villous explant cultures. The influence of E-cadherin loss was examined by analyzing the expression of \u03b15-integrin and phosphorylated focal adhesion kinase (FAK) by Western blot and evaluating trophoblast invasion using a matrigel invasion assay. E-cadherin loss induced the up-regulation of \u03b15-integrin, which leads to the tyrosine phosphorylation of FAK, resulting in an increase in the invasive activity of EVT cells. An \u03b15-integrin neutralizing antibody inhibited the invasion of EVT cells by attenuating FAK tyrosine phosphorylation. Immunohistochemical analysis using clinical placental bed biopsies revealed that \u03b15-integrin was up-regulated and FAK tyrosine phosphorylated (Try861) as EVT cells invade the uterine myometrium, whereas E-cadherin expression was down-regulated. These results suggest that \u03b15-integrin up-regulation induced by E-cadherin loss under hypoxia has a crucial role in regulating the migration of EVT cells. This finding should help us reach a better understanding of the pathogenesis of critical gestational diseases, such as preeclampsia.<\/jats:p>","DOI":"10.1210\/en.2008-1662","type":"journal-article","created":{"date-parts":[[2009,6,5]],"date-time":"2009-06-05T00:46:32Z","timestamp":1244162792000},"page":"4306-4315","source":"Crossref","is-referenced-by-count":49,"title":["Up-Regulation of \u03b15-Integrin by E-Cadherin Loss in Hypoxia and Its Key Role in the Migration of Extravillous Trophoblast Cells during Early Implantation"],"prefix":"10.1210","volume":"150","author":[{"given":"Emi","family":"Arimoto-Ishida","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology (E.A.-I., M.S., K.S., F.N., S.M., T.T., A.I., K.-i.M., T.K.), Osaka University Graduate School of Medicine, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Sakata","sequence":"first","affiliation":[{"name":"Department of Obstetrics and 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