{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T06:07:57Z","timestamp":1777529277803,"version":"3.51.4"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2016,11,1]],"date-time":"2016-11-01T00:00:00Z","timestamp":1477958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":["rep.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Aberrant placental angiogenesis is associated with fetal growth restriction (FGR). In mice, targeted disruption of the homeobox gene, transforming growth \u03b2-induced factor (Tgif-1), which is also a transcription factor, causes defective placental vascularisation. Nevertheless, the role of TGIF-1 in human placental angiogenesis is unclear. We have previously reported increased TGIF-1 expression in human FGR placentae and demonstrated localisation of TGIF-1 protein in placental endothelial cells (ECs). However, its functional role remains to be investigated. In this study, we aimed to specifically compare TGIF-1 mRNA expression in placental ECs isolated from human FGR-affected pregnancies with gestation-matched control pregnancies in two independent cohorts from Australia and Canada and to identify the functional role of TGIF-1 in placental angiogenesis using the human umbilical vein endothelial cell-derived cell line, SGHEC-7, and primary human umbilical vein ECs. Real-time PCR revealed that TGIF-1 mRNA expression was significantly increased in ECs isolated from FGR-affected placentae compared with that of controls. The functional roles of TGIF-1 were determined in ECs after TGIF-1 siRNA transfection. TGIF-1 inactivation in ECs significantly reduced TGIF-1 at both the mRNA and protein levels, as well as the proliferative and invasive potential, but significantly increased the angiogenic potential. Using angiogenesis PCR screening arrays, we identified ITGAV, NRP-1, ANPGT-1 and ANPGT-2 as novel downstream targets of TGIF-1, after TGIF-1 inactivation in ECs. Collectively, these results show that TGIF-1 regulates EC function and the expression of angiogenic molecules; and when abnormally expressed, may contribute to the aberrant placental angiogenesis observed in FGR.<\/jats:p>","DOI":"10.1530\/rep-16-0068","type":"journal-article","created":{"date-parts":[[2016,8,18]],"date-time":"2016-08-18T21:59:55Z","timestamp":1471557595000},"page":"457-465","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":5,"title":["Homeobox gene\n                    <i>TGIF-1<\/i>\n                    is increased in placental endothelial cells of human fetal growth restriction"],"prefix":"10.1093","volume":"152","author":[{"given":"Tilini","family":"Gunatillake","sequence":"first","affiliation":[{"name":"Department of Maternal-Fetal Medicine Pregnancy Research Centre The Royal Women\u2019s Hospital, Parkville, Victoria, Australia"},{"name":"Department of Obstetrics and Gynaecology The University of Melbourne, Parkville, Victoria, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah E J","family":"Yong","sequence":"additional","affiliation":[{"name":"Department of Maternal-Fetal Medicine Pregnancy Research Centre The Royal Women\u2019s Hospital, Parkville, Victoria, Australia"},{"name":"Department of Obstetrics and Gynaecology The University of Melbourne, Parkville, Victoria, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline E","family":"Dunk","sequence":"additional","affiliation":[{"name":"Lunenfeld Tanenbaum-Research Institute Mount Sinai Hospital, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosemary J","family":"Keogh","sequence":"additional","affiliation":[{"name":"Department of Maternal-Fetal Medicine Pregnancy Research Centre The Royal Women\u2019s Hospital, Parkville, Victoria, Australia"},{"name":"Department of Obstetrics and Gynaecology The University of Melbourne, Parkville, Victoria, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony J","family":"Borg","sequence":"additional","affiliation":[{"name":"Department of Maternal-Fetal Medicine Pregnancy Research Centre The Royal Women\u2019s Hospital, Parkville, Victoria, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith E","family":"Cartwright","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular and Cell Sciences St George\u2019s, University of London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guy S","family":"Whitley","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular and Cell Sciences St George\u2019s, University of London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Padma","family":"Murthi","sequence":"additional","affiliation":[{"name":"Department of Maternal-Fetal Medicine Pregnancy Research Centre The Royal Women\u2019s Hospital, Parkville, Victoria, Australia"},{"name":"Department of Obstetrics and Gynaecology The University of Melbourne, Parkville, Victoria, Australia"},{"name":"Department of Medicine School of Clinical Sciences, Monash University, Clayton, Victoria, Australia"},{"name":"The Ritchie Centre Hudson Institute of Medical Research, Clayton, Victoria, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2016,11,1]]},"reference":[{"key":"2026010712451076000_bib1","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1038\/nprot.2010.6","article-title":"In vitro angiogenesis: endothelial cell tube formation on gelled basement membrane extract","volume":"5","author":"Arnaoutova","year":"2010","journal-title":"Nature Protocols"},{"key":"2026010712451076000_bib2","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1523\/JNEUROSCI.5648-11.2012","article-title":"Defective retinal vascular endothelial cell development as a consequence of impaired integrin alphaVbeta8-mediated activation of transforming growth factor-beta","volume":"32","author":"Arnold","year":"2012","journal-title":"Journal of Neuroscience"},{"key":"2026010712451076000_bib3","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.ydbio.2008.04.027","article-title":"Maternal Tgif is required for vascularization of the embryonic placenta","volume":"319","author":"Bartholin","year":"2008","journal-title":"Developmental Biology"},{"key":"2026010712451076000_bib4","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1023\/A:1012259529167","article-title":"Endothelium in vitro: a review of human vascular endothelial cell lines for blood vessel-related research","volume":"4","author":"Bouis","year":"2001","journal-title":"Angiogenesis"},{"key":"2026010712451076000_bib5","doi-asserted-by":"crossref","first-page":"291","DOI":"10.5694\/mja11.11331","article-title":"Australian national birthweight percentiles by sex and gestational age, 1998\u20132007","volume":"197","author":"Dobbins","year":"2012","journal-title":"Medical Journal of Australia"},{"key":"2026010712451076000_bib6","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1139\/y06-091","article-title":"Regulation and function of homeodomain proteins in the embryonic and adult vascular systems","volume":"85","author":"Douville","year":"2007","journal-title":"Canadian Journal of Physiology and Pharmacology"},{"key":"2026010712451076000_bib7","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.fertnstert.2003.09.040","article-title":"Expression of angiopoietin 1 and 2 in ectopic endometrium on the chicken chorioallantoic membrane","volume":"81","author":"Drenkhahn","year":"2004","journal-title":"Fertility and Sterility"},{"key":"2026010712451076000_bib8","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1016\/S0002-9440(10)65089-4","article-title":"Angiopoietin-1 and angiopoietin-2 activate trophoblast Tie-2 to promote growth and migration during placental development","volume":"156","author":"Dunk","year":"2000","journal-title":"American Journal of Pathology"},{"key":"2026010712451076000_bib9","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.placenta.2011.12.020","article-title":"A distinct microvascular endothelial gene expression profile in severe IUGR placentas","volume":"33","author":"Dunk","year":"2012","journal-title":"Placenta"},{"key":"2026010712451076000_bib10","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1038\/emboj.2008.109","article-title":"Identification of PCTA, a TGIF antagonist that promotes PML function in TGF-beta signalling","volume":"27","author":"Faresse","year":"2008","journal-title":"EMBO Journal"},{"key":"2026010712451076000_bib11","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/0014-4827(92)90303-P","article-title":"Characterization of human umbilical vein endothelial cell lines produced by transfection with the early region of SV40","volume":"201","author":"Fickling","year":"1992","journal-title":"Experimental Cell Research"},{"key":"2026010712451076000_bib12","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.atherosclerosis.2006.07.027","article-title":"Urinary levels of matrix metalloproteinase 9 and 2 and tissue inhibitor of matrix metalloproteinase in patients with coronary artery disease","volume":"194","author":"Fitzsimmons","year":"2007","journal-title":"Atherosclerosis"},{"key":"2026010712451076000_bib13","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1002\/(SICI)1097-4652(199711)173:2<206::AID-JCP22>3.0.CO;2-C","article-title":"Molecular mechanisms of vasculogenesis and embryonic angiogenesis","volume":"173","author":"Flamme","year":"1997","journal-title":"Journal of Cell Physiology"},{"key":"2026010712451076000_bib14","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1161\/01.RES.87.10.865","article-title":"The role of homeobox genes in vascular remodeling and angiogenesis","volume":"87","author":"Gorski","year":"2000","journal-title":"Circulation Research"},{"key":"2026010712451076000_bib15","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1203\/01.pdr.0000185266.23265.87","article-title":"Placental expression of angiopoietin-1, angiopoietin-2 and tie-2 during placental development in an ovine model of placental insufficiency-fetal growth restriction","volume":"58","author":"Hagen","year":"2005","journal-title":"Pediatric Research"},{"key":"2026010712451076000_bib16","doi-asserted-by":"crossref","first-page":"1936","DOI":"10.1161\/01.ATV.0000232542.42968.e3","article-title":"Transcriptional regulators of angiogenesis","volume":"26","author":"Hamik","year":"2006","journal-title":"Arteriosclerosis, Thrombosis, and Vascular Biology"},{"key":"2026010712451076000_bib17","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1042\/bj2960803","article-title":"Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells. Effects of tumour necrosis factor alpha, interleukin 1 and phorbol ester","volume":"296","author":"Hanemaaijer","year":"1993","journal-title":"Biochemical Journal"},{"key":"2026010712451076000_bib18","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1097\/00019052-200304000-00003","article-title":"Mouse models of holoprosencephaly","volume":"16","author":"Hayhurst","year":"2003","journal-title":"Current Opinion in Neurology"},{"key":"2026010712451076000_bib19","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/1741-7007-5-47","article-title":"Classification and nomenclature of all human homeobox genes","volume":"5","author":"Holland","year":"2007","journal-title":"BMC Biology"},{"key":"2026010712451076000_bib20","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1016\/S1357-2725(97)00061-7","article-title":"Human microvascular endothelial cells differ from macrovascular endothelial cells in their expression of matrix metalloproteinases","volume":"29","author":"Jackson","year":"1997","journal-title":"International Journal of Biochemistry & Cell Biology"},{"key":"2026010712451076000_bib21","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.placenta.2003.10.009","article-title":"Aspects of human fetoplacental vasculogenesis and angiogenesis. II. Changes during normal pregnancy","volume":"25","author":"Kaufmann","year":"2004","journal-title":"Placenta"},{"key":"2026010712451076000_bib22","doi-asserted-by":"crossref","first-page":"2196","DOI":"10.1002\/cncr.10936","article-title":"Neuropilin 1 and neuropilin 2 co-expression is significantly correlated with increased vascularity and poor prognosis in nonsmall cell lung carcinoma","volume":"95","author":"Kawakami","year":"2002","journal-title":"Cancer"},{"key":"2026010712451076000_bib23","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0301-2115(00)00423-1","article-title":"Development of the placental villous tree and its consequences for fetal growth","volume":"92","author":"Kingdom","year":"2000","journal-title":"European Journal of Obstetrics, Gynecology, and Reproductive Biology"},{"key":"2026010712451076000_bib24","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/S1357-2725(97)00085-X","article-title":"Transcription factors: an overview","volume":"29","author":"Latchman","year":"1997","journal-title":"International Journal of Biochemistry & Cell Biology"},{"key":"2026010712451076000_bib25","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1165\/rcmb.2009-0021OC","article-title":"Transcription factor GATA-6 is expressed in quiescent myofibroblasts in idiopathic pulmonary fibrosis","volume":"42","author":"Lepparanta","year":"2010","journal-title":"American Journal of Respiratory Cell and Molecular Biology"},{"key":"2026010712451076000_bib26","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"2026010712451076000_bib27","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1126\/science.277.5322.55","article-title":"Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis","volume":"277","author":"Maisonpierre","year":"1997","journal-title":"Science"},{"key":"2026010712451076000_bib28","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.ajog.2015.09.068","article-title":"Downregulation of placental neuropilin-1 in fetal growth restriction","volume":"214","author":"Maulik","year":"2016","journal-title":"American Journal of Obstetrics and Gynecology"},{"key":"2026010712451076000_bib29","doi-asserted-by":"crossref","first-page":"511","DOI":"10.2353\/ajpath.2006.050637","article-title":"Homeobox gene HLX1 expression is decreased in idiopathic human fetal growth restriction","volume":"168","author":"Murthi","year":"2006","journal-title":"American Journal of Pathology"},{"key":"2026010712451076000_bib30","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.placenta.2008.04.006","article-title":"Novel homeobox genes are differentially expressed in placental microvascular endothelial cells compared with macrovascular cells","volume":"29","author":"Murthi","year":"2008","journal-title":"Placenta"},{"key":"2026010712451076000_bib31","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.placenta.2006.02.012","article-title":"Homeobox genes are differentially expressed in macrovascular human umbilical vein endothelial cells and microvascular placental endothelial cells","volume":"28","author":"Murthi","year":"2007","journal-title":"Placenta"},{"key":"2026010712451076000_bib32","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1161\/01.ATV.0000052670.55321.87","article-title":"HEX acts as a negative regulator of angiogenesis by modulating the expression of angiogenesis-related gene in endothelial cells in vitro","volume":"23","author":"Nakagawa","year":"2003","journal-title":"Arteriosclerosis, Thrombosis, and Vascular Biology"},{"key":"2026010712451076000_bib33","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1093\/molehr\/gat042","article-title":"Homeobox gene transforming growth factor beta-induced factor-1 (TGIF-1) is a regulator of villous trophoblast differentiation and its expression is increased in human idiopathic fetal growth restriction","volume":"19","author":"Pathirage","year":"2013","journal-title":"Molecular Human Reproduction"},{"key":"2026010712451076000_bib34","doi-asserted-by":"crossref","first-page":"278","DOI":"10.2353\/ajpath.2010.090187","article-title":"Downstream targets of homeobox gene HLX show altered expression in human idiopathic fetal growth restriction","volume":"176","author":"Rajaraman","year":"2010","journal-title":"American Journal of Pathology"},{"key":"2026010712451076000_bib35","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1095\/biolreprod64.4.1033","article-title":"Angiogenesis in the placenta","volume":"64","author":"Reynolds","year":"2001","journal-title":"Biology of Reproduction"},{"key":"2026010712451076000_bib36","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/35080570","article-title":"Placental development: lessons from mouse mutants","volume":"2","author":"Rossant","year":"2001","journal-title":"Nature Reviews. Genetics"},{"key":"2026010712451076000_bib37","doi-asserted-by":"crossref","first-page":"E30","DOI":"10.1210\/jc.2014-2385","article-title":"Impaired fetoplacental angiogenesis in growth-restricted fetuses with abnormal umbilical artery doppler velocimetry is mediated by aryl hydrocarbon receptor nuclear translocator (ARNT)","volume":"100","author":"Su","year":"2015","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"2026010712451076000_bib38","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0163-7258(98)00005-9","article-title":"Heterogeneity of vascular endothelial cells in normal and disease states","volume":"78","author":"Thorin","year":"1998","journal-title":"Pharmacology Therapy"},{"key":"2026010712451076000_bib39","doi-asserted-by":"crossref","first-page":"5058","DOI":"10.4049\/jimmunol.166.8.5058","article-title":"Identification of novel functional regions important for the activity of HOXB7 in mammalian cells","volume":"166","author":"Yaron","year":"2001","journal-title":"Journal of Immunology"}],"container-title":["Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rep.bioscientifica.com\/view\/journals\/rep\/152\/5\/457.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/reproduction\/article-pdf\/152\/5\/457\/64134254\/457.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/reproduction\/article-pdf\/152\/5\/457\/64134254\/457.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T17:46:07Z","timestamp":1767807967000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/reproduction\/article\/152\/5\/457\/8236218"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,1]]},"references-count":39,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2016,11,1]]}},"URL":"https:\/\/doi.org\/10.1530\/rep-16-0068","relation":{},"ISSN":["1470-1626","1741-7899"],"issn-type":[{"value":"1470-1626","type":"print"},{"value":"1741-7899","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,11,1]]},"published":{"date-parts":[[2016,11,1]]}}}