{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T20:58:23Z","timestamp":1771102703402,"version":"3.50.1"},"reference-count":0,"publisher":"Oxford University Press (OUP)","content-domain":{"domain":["rep.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,9,24]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Proper regulation of extravillous trophoblast (EVT) cell invasion is critical for normal placental development and function. Growth differentiation factor 11 (GDF-11), a member of the transforming growth factor-\u03b2 (TGF-\u03b2) superfamily, has been shown to promote EVT cell invasion, yet the underlying molecular mechanisms remain largely unclear. In this study, RNA sequencing identified angiopoietin-like 4 (ANGPTL4), a multifunctional secreted protein, as a novel downstream target of GDF-11.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments demonstrated that GDF-11 significantly upregulated ANGPTL4 expression in both HTR-8\/SVneo cells and primary human EVT cells. Mechanistically, we found that the type I TGF-\u03b2 receptors ALK4 and ALK5 were essential for mediating the stimulatory effect of GDF-11 on ANGPTL4 expression. Further analysis revealed that SMAD3, but not SMAD2, was the key transcription factor involved in this process. Using both loss- and gain-of-function approaches, we demonstrated that ANGPTL4 was required for GDF-11-induced EVT cell invasion. Importantly, serum levels of GDF-11 were markedly reduced in patients with preeclampsia (PE), a pregnancy disorder associated with shallow trophoblast invasion and poor placentation. Together, our findings uncover a previously unrecognized GDF-11-ANGPTL4 signaling axis that regulates EVT cell invasion and provide new insight into the pathophysiology of PE.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>In brief statement<\/jats:title>\n                      <jats:p>How extravillous trophoblast (EVT) invasion is regulated during placental development remains an important question in reproductive biology. This study demonstrates that growth differentiation factor-11 (GDF-11) promotes EVT invasion by upregulating angiopoietin-like 4 (ANGPTL4) via ALK4\/ALK5-SMAD3 signaling, revealing a novel mechanism in placental biology.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1530\/rep-25-0244","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T09:20:26Z","timestamp":1758705626000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-11","source":"Crossref","is-referenced-by-count":2,"title":["GDF-11 stimulates human extravillous trophoblast cell invasion by upregulating ANGPTL4 expression"],"prefix":"10.1093","author":[{"given":"Ze","family":"Wu","sequence":"first","affiliation":[{"name":"Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lanlan","family":"Fang","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuan","family":"Dang","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiping","family":"Yu","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beibei","family":"Bi","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyu","family":"Han","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3783-6509","authenticated-orcid":true,"given":"Ying-Pu","family":"Sun","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5399-9327","authenticated-orcid":true,"given":"Jung-Chien","family":"Cheng","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","container-title":["Reproduction"],"original-title":[],"link":[{"URL":"https:\/\/rep.bioscientifica.com\/view\/journals\/rep\/aop\/REP-25-0244\/REP-25-0244.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/rep.bioscientifica.com\/downloadpdf\/journals\/rep\/aop\/REP-25-0244\/REP-25-0244.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rep.bioscientifica.com\/downloadpdf\/journals\/rep\/aop\/REP-25-0244\/REP-25-0244.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T23:03:42Z","timestamp":1767567822000},"score":1,"resource":{"primary":{"URL":"https:\/\/rep.bioscientifica.com\/view\/journals\/rep\/aop\/REP-25-0244\/REP-25-0244.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,24]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1530\/rep-25-0244","relation":{},"ISSN":["1470-1626","1741-7899"],"issn-type":[{"value":"1470-1626","type":"print"},{"value":"1741-7899","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,24]]}}}