{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T06:40:08Z","timestamp":1780468808110,"version":"3.54.1"},"reference-count":48,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T00:00:00Z","timestamp":1690416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"internal fund of Braude Engineering College"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Placental protein 13 (PP13) is a regulatory protein involved in remodeling the vascular system of the pregnancy and extending the immune tolerance of the mother to the growing fetus. PP13 is localized on the surface of the syncytiotrophoblast. An ex vivo placental model shows that the PP13 is released via placental-associated extracellular vesicles (PEVs) to the maternal uterine vein. This exploratory study aimed to determine PEV-associated PP13 in the maternal circulation as compared to the known soluble fraction since each has a specific communication pathway. Patients admitted to Bnai Zion Medical Center for delivery were recruited, and included 19 preeclampsia (PE) patients (7 preterm PE gestational age &lt; 37 weeks\u2019 gestation), 16 preterm delivery (PTD, delivery at GA &lt; 37 weeks\u2019 gestation), and 15 matched term delivery controls. Treatment by corticosteroids (Celestone), which is often given to patients with suspected preterm PE and PTD, was recorded. The PEV proteome was purified from the patients\u2019 plasma by size exclusion chromatography (SEC) to separate the soluble and PEV-associated PP13. The total level of PP13 (soluble and PEV-associated) was determined using mild detergent that depleted the PEV proteome. PP13 fractions were determined by ELISA with PP13 specific antibodies. ELISA with alkaline phosphatase (PLAP)- and cluster differentiation 63 (CD63)-specific antibodies served to verify the placental origin of the PEVs. SPSS was used for statistical analysis. The patients\u2019 medical, pregnancy, and delivery records in all groups were similar except, as expected, that a larger number of PE and PTD patients had smaller babies who were delivered earlier, and the PE patients had hypertension and proteinuria. The SEC analysis detected the presence of PP13 in the cargo of the PEVs and on their surface, in addition to the known soluble fraction. The median soluble PP13 was not significantly different across the PE, PTD, and term delivery control groups. However, after depleting the PEV of their proteome, the total PP13 (soluble and PEV-associated) was augmented in the cases of preterm PE, reaching 2153 pg\/mL [IQR 1866\u20132838] but not in cases of PTD reaching 1576 pg\/mL [1011\u20132014] or term delivery groups reaching 964 pg\/mL [875\u20131636]), p &lt; 0.01. On the surface of the circulating PEV from PTD patients, there was a decrease in PP13. Corticosteroid treatment was accompanied by a massive depletion of PP13 from the PEV, especially in preterm PE patients. This exploratory study is, thus, the first to determine PEV-associated PP13 in maternal circulation, providing a quantitative determination of the soluble and the PEV-associated fractions, and it shows that the latter is the larger. We found an increase in the amount of PP13 carried via the PEV-associated pathway in PE and PTD patients compared to term delivery cases, which was further augmented when the patients were treated with corticosteroids, especially in preterm PE. The signal conveyed by this novel communication pathway warrants further research to investigate these two differential pathways for the liberation of PP13.<\/jats:p>","DOI":"10.3390\/ijms241512051","type":"journal-article","created":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T01:51:47Z","timestamp":1690509107000},"page":"12051","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Augmented Placental Protein 13 in Placental-Associated Extracellular Vesicles in Term and Preterm Preeclampsia Is Further Elevated by Corticosteroids"],"prefix":"10.3390","volume":"24","author":[{"given":"Marina Marks","family":"Kazatsker","sequence":"first","affiliation":[{"name":"Maternal and Fetal Medicine Unit, Department of Obstetrics and Gynecology, Bnai-Zion University Medical Center, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adi","family":"Sharabi-Nov","sequence":"additional","affiliation":[{"name":"Department of Statistics, Tel Hai Academic College, Tel Hai 122103, Israel"},{"name":"Department of Statistics, Ziv Medical Center, Safed 131000, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamutal","family":"Meiri","sequence":"additional","affiliation":[{"name":"Hy-Laboratories Ltd., Rehovot 7670606, Israel"},{"name":"TeleMarpe Ltd., 21 Beit El St., Tel Aviv 6908742, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rami","family":"Sammour","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Medicine Unit, Department of Obstetrics and Gynecology, Bnai-Zion University Medical Center, Haifa 3498838, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marei","family":"Sammar","sequence":"additional","affiliation":[{"name":"Prof. Ephraim Katzir Department of Biotechnology Engineering, Braude Academic College of Engineering, 51 Snunit St., Karmiel 2161002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S6.e1","DOI":"10.1016\/j.ajog.2015.07.050","article-title":"What is the placenta?","volume":"213","author":"Burton","year":"2015","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"531543","DOI":"10.3389\/fimmu.2020.531543","article-title":"Maternal-Fetal Inflammation in the Placenta and the Developmental Origins of Health and Disease","volume":"11","author":"Goldstein","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"348","DOI":"10.3389\/fimmu.2014.00348","article-title":"Placental Protein 13 (PP13)\u2014A Placental Immunoregulatory Galectin Protecting Pregnancy","volume":"5","author":"Than","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/s00428-008-0658-x","article-title":"Placental protein 13 (galectin-13) has decreased placental expression but increased shedding and maternal serum concentrations in patients presenting with preterm pre-eclampsia and HELLP syndrome","volume":"453","author":"Than","year":"2008","journal-title":"Virchows Arch."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S30","DOI":"10.1016\/j.placenta.2010.09.006","article-title":"Placenta-bound and Body Fluid PP13 and its mRNA in Normal Pregnancy Compared to Preeclampsia, HELLP and Preterm Delivery","volume":"32","author":"Sammar","year":"2011","journal-title":"Placenta"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.placenta.2018.04.013","article-title":"Reduced placental protein 13 (PP13) in placental derived syncytiotrophoblast extracellular vesicles in preeclampsia\u2014A novel tool to study the impaired cargo transmission of the placenta to the maternal organs","volume":"66","author":"Sammar","year":"2018","journal-title":"Placenta"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sammar, M., Drobnjak, T., Mandala, M., Gizurarson, S., Huppertz, B., and Meiri, H. (2019). Galectin 13 (PP13) Facilitates Remodeling and Structural Stabilization of Maternal Vessels during Pregnancy. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133192"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1060850","DOI":"10.3389\/fcell.2022.1060850","article-title":"Unfolding the role of placental-derived Extracellular Vesicles in Pregnancy: From homeostasis to pathophysiology","volume":"10","author":"Ortega","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1042\/CS20220149","article-title":"Preeclampsia and syncytiotrophoblast membrane extracellular vesicles (STB-EVs)","volume":"136","author":"Awoyemi","year":"2022","journal-title":"Clin. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"American College of Obstetricians and Gynecologists (2020). Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin Summary, Number 222. Obstet. Gynecol., 135, 1492\u20131495.","DOI":"10.1097\/AOG.0000000000003892"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.preghy.2021.09.008","article-title":"The 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis & management recommendations for international practice","volume":"27","author":"Magee","year":"2021","journal-title":"Pregnancy Hypertens."},{"key":"ref_12","unstructured":"(2017). Managing Complications in Pregnancy and Childbirth: A Guide for Midwives and Doctors, World Health Organization. [2nd ed.]. Available online: http:\/\/apps.who.int\/iris\/betstream\/handle\/10665\/255760\/9789241565493-eng.pdf;sequence=1."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1056\/NEJMoa1704559","article-title":"Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia","volume":"377","author":"Rolnik","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1002\/uog.26032","article-title":"Clinical utility of sFlt-1 and PlGF in screening, prediction, diagnosis and monitoring of pre-eclampsia and fetal growth restriction","volume":"61","author":"Stepan","year":"2023","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"(2016). American College of Obstetricians and Gynecologists\u2019 Committee on Practice Bulletins\u2014Obstetrics Practice Bulletin No. 171: Management of Preterm Labor. Obstet. Gynecol., 128, e155\u2013e164.","DOI":"10.1097\/AOG.0000000000001711"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0140-6736(08)60074-4","article-title":"Epidemiology and causes of preterm birth","volume":"371","author":"Goldenberg","year":"2008","journal-title":"Lancet"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1056\/NEJMoa1516783","article-title":"Antenatal Betamethasone for Women at Risk for Late Preterm Delivery","volume":"374","author":"Thom","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1080\/01443615.2017.1342614","article-title":"Maternal leukocytosis after antenatal corticosteroid administration: A systematic review and meta-analysis","volume":"38","author":"Bauer","year":"2017","journal-title":"J. Obstet. Gynaecol."},{"key":"ref_19","first-page":"CD006764","article-title":"Different corticosteroids and regimens for accelerating fetal lung maturation for babies at risk of preterm birth","volume":"8","author":"Williams","year":"2022","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.siny.2019.05.002","article-title":"Controversies in antenatal corticosteroids","volume":"24","author":"Shanks","year":"2019","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.4103\/1673-5374.241441","article-title":"Magnesium sulfate and fetal neuroprotection: Overview of clinical evidence","volume":"13","author":"Chollat","year":"2018","journal-title":"Neural Regen. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/ijgo.13856","article-title":"Abstracts of the XXIII FIGO World Congress of Gynecology & Obstetrics","volume":"155","author":"Shennan","year":"2021","journal-title":"Int. J. Gynecol. Obstet."},{"key":"ref_23","first-page":"A40","article-title":"Tocolysis increases the release of placental protein 13 (PP13) from the placenta into the maternal blood","volume":"26","author":"Huppertz","year":"2005","journal-title":"Placenta"},{"key":"ref_24","first-page":"25","article-title":"Tocolytic substances damage syncytiotrophoblast demonstrated by the release of placental protein 13 into the maternal circulation","volume":"28","author":"Bartz","year":"2006","journal-title":"Hypertens. Pregnancy"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9731","DOI":"10.1073\/pnas.0903568106","article-title":"A primate subfamily of galectins expressed at the maternal\u2013fetal interface that promote immune cell death","volume":"106","author":"Than","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1177\/1933719111424445","article-title":"Placental Protein 13 and Decidual Zones of Necrosis: An Immunologic Diversion That May be Linked to Preeclampsia","volume":"19","author":"Kliman","year":"2012","journal-title":"Reprod. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1080\/10641955.2017.1295052","article-title":"Placental protein 13 (PP13)-induced vasodilation of resistance arteries from pregnant and nonpregnant rats occurs via endothelial-signaling pathways","volume":"36","author":"Drobnjak","year":"2017","journal-title":"Hypertens. Pregnancy"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"213","DOI":"10.2147\/IJWH.S188303","article-title":"Placental protein 13 (PP13) stimulates rat uterine vessels after slow subcutaneous administration","volume":"11","author":"Drobnjak","year":"2019","journal-title":"Int. J. Women\u2019s Health"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.placenta.2018.02.006","article-title":"Placental exosomes profile in maternal and fetal circulation in intrauterine growth restriction\u2014Liquid biopsies to monitoring fetal growth","volume":"64","author":"Miranda","year":"2018","journal-title":"Placenta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1111\/j.1471-0528.1998.tb10178.x","article-title":"Shedding of syncytiotrophoblast microvilli into the maternal circulation in pre-eclamptic pregnancies","volume":"105","author":"Knight","year":"1998","journal-title":"BJOG: Int. J. Obstet. Gynaecol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ymeth.2015.03.028","article-title":"Isolation of syncytiotrophoblast microvesicles and exosomes and their characterisation by multicolour flow cytometry and fluorescence Nanoparticle Tracking Analysis","volume":"87","author":"Dragovic","year":"2015","journal-title":"Methods"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/j.ymthe.2023.02.013","article-title":"Exploiting the biogenesis of extracellular vesicles for bioengineering and therapeutic cargo loading","volume":"31","author":"Gupta","year":"2023","journal-title":"Mol. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s12964-022-00853-z","article-title":"The implications of exosomes in pregnancy: Emerging as new diagnostic markers and therapeutics targets","volume":"20","author":"Ghafourian","year":"2022","journal-title":"Cell Commun. Signal."},{"key":"ref_34","first-page":"471","article-title":"Establishing a Differential Marker Profile for Pregnancy Complications Near Delivery","volume":"47","author":"Kumar","year":"2019","journal-title":"Fetal Diagn. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e11226","DOI":"10.1016\/j.heliyon.2022.e11226","article-title":"Blood biomarkers to predict the onset of pre-eclampsia: A systematic review and meta-analysis","volume":"8","author":"Danielli","year":"2022","journal-title":"Heliyon"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Hornaday, K.K., Wood, E.M., and Slater, D.M. (2022). Is there a maternal blood biomarker that can predict spontaneous preterm birth prior to labour onset? A systematic review. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0265853"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1148\/radiology.182.2.1732970","article-title":"Fetal crown-rump length: Reevaluation of relation to menstrual age (5\u201318 weeks) with high-resolution real-time US","volume":"182","author":"Hadlock","year":"1992","journal-title":"Radiology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/jhh.2009.45","article-title":"Maternal risk factors for hypertensive disorders in pregnancy: A multivariate approach","volume":"24","author":"Poon","year":"2009","journal-title":"J. Hum. Hypertens."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.placenta.2003.12.009","article-title":"Placental protein 13 (PP-13): Effects on cultured trophoblasts, and its detection in human body fluids in normal and pathological pregnancies","volume":"25","author":"Burger","year":"2004","journal-title":"Placenta"},{"key":"ref_40","first-page":"1065","article-title":"Functional analyses of placental protein 13\/galectin","volume":"271","author":"Than","year":"2004","journal-title":"JBIC J. Biol. Inorg. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1002\/uog.2686","article-title":"A novel approach to first-trimester screening for early pre-eclampsia combining serum PP-13 and Doppler ultrasound","volume":"27","author":"Nicolaides","year":"2005","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"35.e1","DOI":"10.1016\/j.ajog.2007.02.025","article-title":"First-trimester placental protein 13 screening for preeclampsia and intrauterine growth restriction","volume":"197","author":"Chafetz","year":"2007","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"122.e1","DOI":"10.1016\/j.ajog.2008.01.013","article-title":"First-trimester maternal serum PP13 in the risk assessment for preeclampsia","volume":"199","author":"Romero","year":"2008","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1111\/j.1471-0528.2008.01902.x","article-title":"Placental protein 13 as an early marker for pre-eclampsia: A prospective longitudinal study","volume":"115","author":"Gonen","year":"2008","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1159\/000151344","article-title":"Longitudinal Determination of Serum Placental Protein 13 during Development of Preeclampsia","volume":"24","author":"Huppertz","year":"2008","journal-title":"Fetal Diagn. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9775","DOI":"10.1039\/C5OB01451D","article-title":"Differential detergent sensitivity of extracellular vesicle subpopulations","volume":"13","author":"Osteikoetxea","year":"2015","journal-title":"Org. Biomol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Than, N.G., Romero, R., Meiri, H., Erez, O., Xu, Y., Tarquini, F., Barna, L., Szilagyi, A., Ackerman, R., and Sammar, M. (2011). PP13, Maternal ABO Blood Groups and the Risk Assessment of Pregnancy Complications. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0021564"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.2147\/DDDT.S167926","article-title":"Pharmacokinetics of placental protein 13 after intravenous and subcutaneous administration in rabbits","volume":"12","author":"Drobnjak","year":"2018","journal-title":"Drug Des. Dev. Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/15\/12051\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:20:45Z","timestamp":1760127645000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/15\/12051"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,27]]},"references-count":48,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["ijms241512051"],"URL":"https:\/\/doi.org\/10.3390\/ijms241512051","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,27]]}}}