{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T16:00:38Z","timestamp":1792425638035,"version":"4.5.0"},"reference-count":69,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2016,1,12]],"date-time":"2016-01-12T00:00:00Z","timestamp":1452556800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["084804\/2\/08\/Z"],"award-info":[{"award-number":["084804\/2\/08\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2016,3]]},"abstract":"Abstract<\/jats:title>Low maternal circulating concentrations of placental growth factor (PlGF<\/jats:styled-content>) are one of the hallmarks of human pregnancy complications, including fetal growth restriction (FGR<\/jats:styled-content>) and early\u2010onset pre\u2010eclampsia (PE<\/jats:styled-content>). Currently, PlGF<\/jats:styled-content> is used clinically with other biomarkers to screen for high\u2010risk cases, although the mechanisms underlying its regulation are largely unknown. Placental endoplasmic reticulum (ER<\/jats:styled-content>) stress has recently been found to be elevated in cases of FGR<\/jats:styled-content>, and to an even greater extent in early\u2010onset PE<\/jats:styled-content> complicated with FGR<\/jats:styled-content>. ER<\/jats:styled-content> stress activates the unfolded protein response (UPR<\/jats:styled-content>); attenuation of protein translation and a reduction in cell growth and proliferation play crucial roles in the pathophysiology of these complications of pregnancy. In this study, we further identified that ER<\/jats:styled-content> stress regulates release of PlGF<\/jats:styled-content>. We first observed that down\u2010regulation of PlGF<\/jats:styled-content> protein was associated with nuclear localization of ATF4<\/jats:styled-content>, ATF6\u03b1<\/jats:styled-content> and ATF6\u03b2<\/jats:styled-content> in the syncytiotrophoblast of placentae from PE<\/jats:styled-content> patients. Transcript analysis showed a decrease of PlGF<\/jats:styled-content><\/jats:italic> mRNA<\/jats:styled-content>, and an increase from genes encoding those UPR<\/jats:styled-content> transcription factors in placentae from cases of early\u2010onset PE<\/jats:styled-content>, but not of late\u2010onset (>34 weeks) PE<\/jats:styled-content>, compared to term controls. Further investigations indicated a strong correlation between ATF4<\/jats:styled-content><\/jats:italic> and PlGF<\/jats:styled-content><\/jats:italic> mRNA<\/jats:styled-content> levels only (r<\/jats:italic> = \u2212 0.73, p <<\/jats:italic> 0.05). These results could be recapitulated in trophoblast\u2010like cells exposed to chemical inducers of ER<\/jats:styled-content> stress or hypoxia\u2013reoxygenation. The stability of PlGF<\/jats:styled-content><\/jats:italic> transcripts was unchanged. The use of small interfering RNA<\/jats:styled-content> specific for transcription factors in the UPR<\/jats:styled-content> pathways revealed that ATF4<\/jats:styled-content> and ATF6\u03b2<\/jats:styled-content>, but not ATF6\u03b1<\/jats:styled-content>, modulate PlGF<\/jats:styled-content><\/jats:italic> transcription. To conclude, ATF4<\/jats:styled-content> and ATF6\u03b2<\/jats:styled-content> act synergistically in the negative regulation of PlGF<\/jats:styled-content><\/jats:italic> mRNA<\/jats:styled-content> expression, resulting in reduced PlGF<\/jats:styled-content> secretion by the trophoblast in response to stress. Therefore, these results further support the targeting of placental ER<\/jats:styled-content> stress as a potential new therapeutic intervention for these pregnancy complications. \u00a9 2015 The Authors. Journal of Pathology<\/jats:italic> published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.4678","type":"journal-article","created":{"date-parts":[[2015,12,9]],"date-time":"2015-12-09T11:51:53Z","timestamp":1449661913000},"page":"550-561","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":100,"title":["Placental endoplasmic reticulum stress negatively regulates transcription of placental growth factor via ATF4 and ATF6\u03b2: implications for the pathophysiology of human pregnancy complications"],"prefix":"10.1002","volume":"238","author":[{"given":"Masahito","family":"Mizuuchi","sequence":"first","affiliation":[{"name":"Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience University of Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tereza","family":"Cindrova\u2010Davies","sequence":"additional","affiliation":[{"name":"Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience University of Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matts","family":"Olovsson","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health Uppsala University Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D Stephen","family":"Charnock\u2010Jones","sequence":"additional","affiliation":[{"name":"Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience University of Cambridge UK"},{"name":"Department of Obstetrics and Gynaecology University of Cambridge, The Rosie Hospital Cambridge UK"},{"name":"National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham J","family":"Burton","sequence":"additional","affiliation":[{"name":"Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience University of Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong Wa","family":"Yung","sequence":"additional","affiliation":[{"name":"Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience University of Cambridge 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