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Up-Regulation Of α5-Integrin By E-Cadherin Loss In Hypoxia And Its Key Role In The Migration Of Extravillous Trophoblast Cells During Early Implantation

Emi Arimoto-Ishida, Masahiro Sakata, Kenjiro Sawada, Masahiro Nakayama, Fumihito Nishimoto, Seiji Mabuchi, Takashi Takeda, Toshiya Yamamoto, Aki Isobe, Yoko Okamoto, Ernst Lengyel, Noriyuki Suehara, Ken-ichirou Morishige, Tadashi Kimura

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AbstractDuring 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 α5-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 α5-integrin, which leads to the tyrosine phosphorylation of FAK, resulting in an increase in the invasive activity of EVT cells. An α5-integrin neutralizing antibody inhibited the invasion of EVT cells by attenuating FAK tyrosine phosphorylation. Immunohistochemical analysis using clinical placental bed biopsies revealed that α5-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 α5-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.