{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T23:19:18Z","timestamp":1790637558229,"version":"4.1.0"},"reference-count":24,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,12]],"date-time":"2021-07-12T00:00:00Z","timestamp":1626048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Biomarkers for placental dysfunction are currently lacking. We recently identified SPINT1 as a novel biomarker; SPINT2 is a functionally related placental protease inhibitor. This study aimed to characterise SPINT2 expression in placental insufficiency. Circulating SPINT2 was assessed in three prospective cohorts, collected at the following: (1) term delivery (n = 227), (2) 36 weeks (n = 364), and (3) 24\u201334 weeks\u2019 (n = 294) gestation. SPINT2 was also measured in the plasma and placentas of women with established placental disease at preterm (&lt;34 weeks) delivery. Using first-trimester human trophoblast stem cells, SPINT2 expression was assessed in hypoxia\/normoxia (1% vs. 8% O2), and following inflammatory cytokine treatment (TNF\u03b1, IL-6). Placental SPINT2 mRNA was measured in a rat model of late-gestational foetal growth restriction. At 36 weeks, circulating SPINT2 was elevated in patients who later developed preeclampsia (p = 0.028; median = 2233 pg\/mL vs. controls, median = 1644 pg\/mL), or delivered a small-for-gestational-age infant (p = 0.002; median = 2109 pg\/mL vs. controls, median = 1614 pg\/mL). SPINT2 was elevated in the placentas of patients who required delivery for preterm preeclampsia (p = 0.025). Though inflammatory cytokines had no effect, hypoxia increased SPINT2 in cytotrophoblast stem cells, and its expression was elevated in the placental labyrinth of growth-restricted rats. These findings suggest elevated SPINT2 is associated with placental insufficiency.<\/jats:p>","DOI":"10.3390\/ijms22147467","type":"journal-article","created":{"date-parts":[[2021,7,12]],"date-time":"2021-07-12T21:56:37Z","timestamp":1626126997000},"page":"7467","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Elevated Circulating and Placental SPINT2 Is Associated with Placental Dysfunction"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6996-7250","authenticated-orcid":false,"given":"Ciara N.","family":"Murphy","sequence":"first","affiliation":[{"name":"The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, The University of Melbourne, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan P.","family":"Walker","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, The University of Melbourne, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9099-7745","authenticated-orcid":false,"given":"Teresa M.","family":"MacDonald","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, The University of Melbourne, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1966-2293","authenticated-orcid":false,"given":"Emerson","family":"Keenan","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, The University of Melbourne, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie J.","family":"Hannan","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, The University of Melbourne, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8490-9099","authenticated-orcid":false,"given":"Mary E.","family":"Wlodek","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, The University of Melbourne, Heidelberg, VIC 3084, Australia"},{"name":"The Department of Anatomy and Physiology, The University of Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Myers","sequence":"additional","affiliation":[{"name":"Manchester Academic Health Science Centre, St Mary\u2019s Hospital, University of Manchester, Manchester M13 OJH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica F.","family":"Briffa","sequence":"additional","affiliation":[{"name":"The Department of Anatomy and Physiology, The University of Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8581-2256","authenticated-orcid":false,"given":"Tania","family":"Romano","sequence":"additional","affiliation":[{"name":"The Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC 3086, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Roddy Mitchell","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, The University of Melbourne, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole-Anne","family":"Whigham","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, The University of Melbourne, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Cannon","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, The University of Melbourne, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuong-Vi","family":"Nguyen","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, The University of Melbourne, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1317-5232","authenticated-orcid":false,"given":"Manju","family":"Kandel","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, The University of Melbourne, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7388-2193","authenticated-orcid":false,"given":"Natasha","family":"Pritchard","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, The University of Melbourne, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Tong","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, The University of Melbourne, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tu\u2019uhevaha J.","family":"Kaitu\u2019u-Lino","sequence":"additional","affiliation":[{"name":"The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, The University of Melbourne, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, Mercy Hospital for Women, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"f108","DOI":"10.1136\/bmj.f108","article-title":"Maternal and fetal risk factors for stillbirth: Population based study","volume":"346","author":"Gardosi","year":"2013","journal-title":"BMJ"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/S0140-6736(10)62233-7","article-title":"Major risk factors for stillbirth in high-income countries: A systematic review and meta-analysis","volume":"377","author":"Flenady","year":"2011","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Chappell, L.C., A Cluver, C., Kingdom, J., and Tong, S. (2021). Pre-eclampsia. Lancet.","DOI":"10.1016\/S0140-6736(20)32335-7"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1038\/s41467-020-16346-x","article-title":"Circulating SPINT1 is a biomarker of pregnancies with poor placental function and fetal growth re-striction","volume":"11","author":"MacDonald","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6370","DOI":"10.1074\/jbc.272.10.6370","article-title":"Hepatocyte growth factor activator inhibitor, a novel Kunitz-type serine protease inhibitor","volume":"272","author":"Shimomura","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1023\/A:1023051500010","article-title":"Roles of hepatocyte growth factor (HGF) activator and HGF activator inhibitor in the pericellular activation of HGF\/scatter factor","volume":"22","author":"Kataoka","year":"2003","journal-title":"Cancer Metastasis Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.cytogfr.2009.05.004","article-title":"Cytokine regulation during the formation of the fetal\u2013maternal interface: Focus on cell-cell adhesion and remodelling of the extra-cellular matrix","volume":"20","author":"McEwan","year":"2009","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.placenta.2005.08.006","article-title":"Metalloproteinases and human placental invasiveness","volume":"27","author":"Cohen","year":"2006","journal-title":"Placenta"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S745","DOI":"10.1016\/j.ajog.2017.11.577","article-title":"Pathophysiology of placental-derived fetal growth restriction","volume":"218","author":"Burton","year":"2018","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.placenta.2009.02.009","article-title":"Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy","volume":"30","author":"Burton","year":"2009","journal-title":"Placenta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"27558","DOI":"10.1074\/jbc.272.44.27558","article-title":"Purification and cloning of hepatocyte growth factor activator inhibitor type 2, a Kunitz-type serine protease inhibitor","volume":"272","author":"Kawaguchi","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2653","DOI":"10.1242\/dev.038430","article-title":"Regulation of cell surface protease matriptase by HAI2 is essential for placental development, neural tube closure and embryonic survival in mice","volume":"136","author":"Szabo","year":"2009","journal-title":"Development"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1007\/s13577-012-0055-2","article-title":"Regulation of pericellular proteolysis by hepatocyte growth factor activator inhibitor type 1 (HAI-1) in trophoblast cells","volume":"25","author":"Kohama","year":"2012","journal-title":"Hum. Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2818","DOI":"10.1242\/dev.137968","article-title":"Delineation of proteolytic and non-proteolytic functions of membrane-anchored serine protease Prss8\/prostasin","volume":"143","author":"Szabo","year":"2016","journal-title":"Development"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1293\/tox.2018-0042","article-title":"Morphology and physiology of rat placenta for toxicological evaluation","volume":"32","author":"Furukawa","year":"2019","journal-title":"J. Toxicol. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3351","DOI":"10.1046\/j.1432-1327.2000.01368.x","article-title":"Genomic structure and chromosomal localization of the human hepatocyte growth factor activator inhibitor type 1 and 2 genes","volume":"267","author":"Itoh","year":"2000","journal-title":"Eur. J. Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1158\/1078-0432.CCR-06-1266","article-title":"Regulation of hepatocyte growth factor activator inhibitor 2 by hypoxia in breast cancer","volume":"13","author":"Generali","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"American College of Obstetricians and Gynecologists (2020). Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin, Number 222. Obstet. Gynecol., 135, e237\u2013e260.","DOI":"10.1097\/AOG.0000000000003891"},{"key":"ref_19","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":"Med. J. Aust."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3389","DOI":"10.1113\/JP273825","article-title":"Uteroplacental insufficiency reduces rat plasma leptin concentrations and alters placental leptin transporters: Ameliorated with enhanced milk intake and nutrition","volume":"595","author":"Briffa","year":"2017","journal-title":"J. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"R1620","DOI":"10.1152\/ajpregu.00789.2004","article-title":"Uteroplacental restriction in the rat impairs fetal growth in association with alterations in placental growth factors including PTHrP","volume":"288","author":"Wlodek","year":"2005","journal-title":"Am. J. Physiol. Integr. Comp. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.stem.2017.11.004","article-title":"Derivation of human trophoblast stem cells","volume":"22","author":"Okae","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1002\/bies.201500087","article-title":"The basal chorionic trophoblast cell layer: An emerging coordinator of placenta development","volume":"38","author":"Walentin","year":"2016","journal-title":"BioEssays"},{"key":"ref_24","first-page":"287","article-title":"Characterization of protocols for primary trophoblast purification, optimized for functional inves-tigation of sFlt-1 and soluble endoglin","volume":"4","author":"Tong","year":"2014","journal-title":"Pregnancy Hypertens. Int. J. Women\u2019s Cardiovasc. Health"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7467\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:29:24Z","timestamp":1760164164000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7467"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,12]]},"references-count":24,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22147467"],"URL":"https:\/\/doi.org\/10.3390\/ijms22147467","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,12]]}}}