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Up-Regulation of ₅-Integrin by E-Cadherin Loss in Hypoxia and Its Key Role in the Migration of Extravillous Trophoblast Cells during Early Implantation

Departments 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; Osaka Medical Center and Research Institute for Maternal and Child Health (M.N., Y.O., N.S.), Osaka 594-1101, Japan; Department of Obstetrics and Gynecology (T.Y.), Sakai Municipal Hospital, Osaka 591-0064, Japan; and Department of Obstetrics and Gynecology/Section of Gynecologic Oncology (E.L.), University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Masahiro Sakata, M.D., Ph.D., Departments of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: msakata{at}gyne.med.osaka-u.ac.jp.

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 ₅-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 ₅-integrin, which leads to the tyrosine phosphorylation of FAK, resulting in an increase in the invasive activity of EVT cells. An ₅-integrin neutralizing antibody inhibited the invasion of EVT cells by attenuating FAK tyrosine phosphorylation. Immunohistochemical analysis using clinical placental bed biopsies revealed that ₅-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 ₅-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.