title: Up-regulation of alpha5-integrin by E-cadherin loss in hypoxia and its key role in the migration of extravillous trophoblast cells during early implantation.
abstract: 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 alpha(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 alpha(5)-integrin, which leads to the tyrosine phosphorylation of FAK, resulting in an increase in the invasive activity of EVT cells. An alpha(5)-integrin neutralizing antibody inhibited the invasion of EVT cells by attenuating FAK tyrosine phosphorylation. Immunohistochemical analysis using clinical placental bed biopsies revealed that alpha(5)-integrin was up-regulated and FAK tyrosine phosphorylated (Try(861)) as EVT cells invade the uterine myometrium, whereas E-cadherin expression was down-regulated. These results suggest that alpha(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.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine,Suita, Osaka 565-0871, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Arimoto-Ishida
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakata
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Sawada
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakayama
authors.forename: Fumihito
authors.initials: F
authors.lastname: Nishimoto
authors.forename: Seiji
authors.initials: S
authors.lastname: Mabuchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Takeda
authors.forename: Toshiya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Aki
authors.initials: A
authors.lastname: Isobe
authors.forename: Yoko
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Ernst
authors.initials: E
authors.lastname: Lengyel
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Suehara
authors.forename: Ken-Ichirou
authors.initials: K
authors.lastname: Morishige
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kimura
mesh_terms: D015820:Cadherins / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D010064:Embryo Implantation; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D039482:Integrin alpha5 / Q000378:metabolism*; D010766:Phosphorylation; D011247:Pregnancy; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis; D014327:Trophoblasts / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D015820:Cadherins; D039482:Integrin alpha5; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051416:Focal Adhesion Protein-Tyrosine Kinases