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However, whether integrin \u03b21 mediates activin A\u2010increased trophoblast invasion remains unknown and the evidence is limited regarding the predictive value of activin A for PE\/PIH in women receiving in vitro fertilization (IVF) treatment. Here, we studied the role and underlying molecular mechanisms of integrin \u03b21 in activin A\u2010promoted invasion in immortalized (HTR8\/SVneo) and primary human extravillous trophoblast (EVT) cells. A nest case\u2010control study was designed to investigate the predictive\/diagnostic value of activin A in IVF pregnancies. Results showed that integrin \u03b21 expression increased after activin A treatment and knockdown of integrin \u03b21 significantly decreased both basal and activin A\u2010increased HTR8\/SVneo cell invasion. SB431542 (TGF\u2010\u03b2 type I receptors inhibitor) abolished activin A\u2010induced SMAD2\/SMAD3 phosphorylation and integrin \u03b21 overexpression. Activin A\u2010upregulated integrin \u03b21 expression was attenuated after the depletion of ALK4 or SMAD4 in both HTR8\/SVneo and primary EVT cells. Furthermore, we found similar first\u2010trimester activin A levels in IVF patients with or without subsequent PE\/PIH. These results reveal that integrin \u03b21 mediates activin A\u2010promoted trophoblast invasion through ALK4\u2010activated SMAD2\/3\u2010SMAD4 pathway, and the predictive\/diagnostic value of first\u2010trimester maternal serum activin A for hypertensive disorders of pregnancy might be different in IVF population.<\/jats:p>","DOI":"10.1096\/fj.202001604r","type":"journal-article","created":{"date-parts":[[2020,11,24]],"date-time":"2020-11-24T00:59:12Z","timestamp":1606179552000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Activin A increases human trophoblast invasion by upregulating integrin \u03b21 through ALK4"],"prefix":"10.1096","volume":"35","author":[{"given":"Shiqin","family":"Zhu","sequence":"first","affiliation":[{"name":"Center for Reproductive Medicine Cheeloo College of Medicine, Shandong University Jinan China"},{"name":"National Research Center for Assisted Reproductive Technology and Reproductive Genetics Shandong University Jinan China"},{"name":"Key Laboratory of Reproductive Endocrinology of Ministry of Education Shandong University Jinan China"},{"name":"Shandong Provincial Clinical Medicine Research Center for Reproductive Health Shandong University Jinan China"},{"name":"School of Medicine Shandong University Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Medicine Shandong University Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linlin","family":"Cui","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine Cheeloo College of Medicine, Shandong University Jinan China"},{"name":"National Research Center for Assisted Reproductive Technology and Reproductive Genetics Shandong University Jinan China"},{"name":"Key Laboratory of Reproductive Endocrinology of Ministry of Education Shandong University Jinan China"},{"name":"Shandong Provincial Clinical Medicine Research Center for Reproductive Health Shandong University Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Ban","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Qilu Hospital of Shandong University Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3152-3800","authenticated-orcid":false,"given":"Peter C. K.","family":"Leung","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology BC Children\u2019s Hospital Research Institute, University of British Columbia Vancouver BC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1813-8115","authenticated-orcid":false,"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine Cheeloo College of Medicine, Shandong University Jinan China"},{"name":"National Research Center for Assisted Reproductive Technology and Reproductive Genetics Shandong University Jinan China"},{"name":"Key Laboratory of Reproductive Endocrinology of Ministry of Education Shandong University Jinan China"},{"name":"Shandong Provincial Clinical Medicine Research Center for Reproductive Health Shandong University Jinan China"},{"name":"School of Medicine Shandong University Jinan 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