{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:59:30Z","timestamp":1787317170203,"version":"build-2736575974"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T00:00:00Z","timestamp":1701820800000},"content-version":"vor","delay-in-days":7,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Health Research Council of New Zealand Sir Charles Hercus Research Fellowship"},{"name":"University of Auckland Doctoral Scholarship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,11,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Growth-restricted placentae have a reduced vascular network, impairing exchange of nutrients and oxygen. However, little is known about the differentiation events and cell types that underpin normal\/abnormal placental vascular formation and function. Here, we used 23-colour flow cytometry to characterize placental vascular\/perivascular populations between first trimester and term, and in foetal growth restriction (FGR). First-trimester endothelial cells had an immature phenotype (CD144+\/lowCD36\u2212CD146low), while term endothelial cells expressed mature endothelial markers (CD36+CD146+). At term, a distinct population of CD31low endothelial cells co-expressed mesenchymal markers (CD90, CD26), indicating a capacity for endothelial to mesenchymal transition (EndMT). In FGR, compared with normal pregnancies, endothelial cells constituted 3-fold fewer villous core cells (P\u2009&amp;lt;\u20090.05), contributing to an increased perivascular: endothelial cell ratio (2.6-fold, P\u2009&amp;lt;\u20090.05). This suggests that abnormal EndMT may play a role in FGR. First-trimester endothelial cells underwent EndMT in culture, losing endothelial (CD31, CD34, CD144) and gaining mesenchymal (CD90, CD26) marker expression. Together this highlights how differences in villous core cell heterogeneity and phenotype may contribute to FGR pathophysiology across gestation.<\/jats:p>","DOI":"10.1093\/molehr\/gaad041","type":"journal-article","created":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T02:05:44Z","timestamp":1701655544000},"source":"Crossref","is-referenced-by-count":8,"title":["Human placental vascular and perivascular cell heterogeneity differs between first trimester and term, and in pregnancies affected by foetal growth restriction"],"prefix":"10.1093","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1943-4162","authenticated-orcid":false,"given":"Anna L","family":"Boss","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medical and Health Sciences, University of Auckland , Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7501-1340","authenticated-orcid":false,"given":"Lawrence W","family":"Chamley","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medical and Health Sciences, University of Auckland , Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna E S","family":"Brooks","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Auckland , Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna L","family":"James","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medical and Health Sciences, University of Auckland , Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,12,6]]},"reference":[{"key":"2023122305010425600_gaad041-B1","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/nrm2183","article-title":"Molecular regulation of angiogenesis and lymphangiogenesis","volume":"8","author":"Adams","year":"2007","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2023122305010425600_gaad041-B2","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.2353\/ajpath.2008.071194","article-title":"Capillary sprout endothelial cells exhibit a CD36low phenotype: regulation by shear stress and vascular endothelial growth factor-induced mechanism for attenuating anti-proliferative thrombospondin-1 signaling","volume":"173","author":"Anderson","year":"2008","journal-title":"Am J Pathol"},{"key":"2023122305010425600_gaad041-B3","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.placenta.2015.01.389","article-title":"Vascular regression in the fetoplacental vascular bed, and its possible implications for fetal growth restriction","volume":"36","author":"Aplin","year":"2015","journal-title":"Placenta"},{"key":"2023122305010425600_gaad041-B4","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1093\/ije\/31.6.1235","article-title":"Fetal origins of adult disease: strength of effects and biological basis","volume":"31","author":"Barker","year":"2002","journal-title":"Int J Epidemiol"},{"key":"2023122305010425600_gaad041-B5","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1002\/jemt.20120","article-title":"Ultrastructural study on human placenta from intrauterine growth retardation cases","volume":"65","author":"Battistelli","year":"2004","journal-title":"Microsc Res Tech"},{"key":"2023122305010425600_gaad041-B6","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.76622","article-title":"Full spectrum flow cytometry reveals mesenchymal heterogeneity in first trimester placentae and phenotypic convergence in culture, providing insight into the origins of placental mesenchymal stromal cells","volume":"11","author":"Boss","year":"2022","journal-title":"Elife"},{"key":"2023122305010425600_gaad041-B7","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.placenta.2004.06.007","article-title":"Immunocytological evidence for hematopoiesis in the early human placenta","volume":"26","author":"Challier","year":"2005","journal-title":"Placenta"},{"key":"2023122305010425600_gaad041-B8","doi-asserted-by":"crossref","first-page":"679995","DOI":"10.3389\/fcell.2021.679995","article-title":"New technologies with increased precision improve understanding of endothelial cell heterogeneity in cardiovascular health and disease","volume":"9","author":"Dawson","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"2023122305010425600_gaad041-B9","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1083\/jcb.138.3.707","article-title":"CD36 mediates the in vitro inhibitory effects of thrombospondin-1 on endothelial cells","volume":"138","author":"Dawson","year":"1997","journal-title":"J Cell Biol"},{"key":"2023122305010425600_gaad041-B10","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.placenta.2005.05.011","article-title":"Sequential steps during vasculogenesis and angiogenesis in the very early human placenta","volume":"27","author":"Demir","year":"2006","journal-title":"Placenta"},{"key":"2023122305010425600_gaad041-B11","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1038\/s41467-017-01738-3","article-title":"Pericytes regulate VEGF-induced endothelial sprouting through VEGFR1","volume":"8","author":"Eilken","year":"2017","journal-title":"Nat Commun"},{"key":"2023122305010425600_gaad041-B12","doi-asserted-by":"crossref","first-page":"11853","DOI":"10.1038\/ncomms11853","article-title":"Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability","volume":"7","author":"Evrard","year":"2016","journal-title":"Nat Commun"},{"key":"2023122305010425600_gaad041-B13","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1111\/j.0001-6349.2004.00602.x","article-title":"Restricted fetal growth in sudden intrauterine unexplained death","volume":"83","author":"Froen","year":"2004","journal-title":"Acta Obstet Gynecol Scand"},{"key":"2023122305010425600_gaad041-B14","doi-asserted-by":"crossref","first-page":"4213","DOI":"10.1210\/jc.2002-020195","article-title":"Human placental vascular development: vasculogenic and angiogenic (branching and nonbranching) transformation is regulated by vascular endothelial growth factor-A, angiopoietin-1, and angiopoietin-2","volume":"87","author":"Geva","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2023122305010425600_gaad041-B15","first-page":"661","article-title":"Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement","author":"Gnecchi","year":"2006"},{"key":"2023122305010425600_gaad041-B16","first-page":"103","article-title":"Vascular network modeling reveals significant differences in vascular morphology in growth-restricted placentas","volume":"4","author":"Gong","year":"2011","journal-title":"Rev Obstet Gynecol"},{"key":"2023122305010425600_gaad041-B17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.placenta.2020.10.032","article-title":"Pericytes on placental capillaries in terminal villi preferentially cover endothelial junctions in regions furthest away from the trophoblast","volume":"104","author":"Harris","year":"2020","journal-title":"Placenta"},{"key":"2023122305010425600_gaad041-B18","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1530\/REP-14-0646","article-title":"Isolation and characterisation of a novel trophoblast side-population from first trimester placentae","volume":"150","author":"James","year":"2015","journal-title":"Reproduction"},{"key":"2023122305010425600_gaad041-B19","doi-asserted-by":"crossref","first-page":"3077","DOI":"10.1113\/JP270495","article-title":"Dysregulated flow-mediated vasodilatation in the human placenta in fetal growth restriction","volume":"593","author":"Jones","year":"2015","journal-title":"J Physiol"},{"key":"2023122305010425600_gaad041-B20","doi-asserted-by":"crossref","first-page":"4144","DOI":"10.1038\/s41598-017-04379-0","article-title":"Whole organ vascular casting and microCT examination of the human placental vascular tree reveals novel alterations associated with pregnancy disease","volume":"7","author":"Junaid","year":"2017","journal-title":"Sci Rep"},{"key":"2023122305010425600_gaad041-B21","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.placenta.2014.07.013","article-title":"Fetoplacental vascular alterations associated with fetal growth restriction","volume":"35","author":"Junaid","year":"2014","journal-title":"Placenta"},{"key":"2023122305010425600_gaad041-B22","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.jacc.2018.09.089","article-title":"Endothelial to mesenchymal transition in cardiovascular disease: JACC state-of-the-art review","volume":"73","author":"Kovacic","year":"2019","journal-title":"J Am Coll Cardiol"},{"key":"2023122305010425600_gaad041-B23","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1016\/S0002-9378(96)70103-5","article-title":"Intrauterine growth restriction with absent end-diastolic flow velocity in the umbilical artery is associated with maldevelopment of the placental terminal villous tree","volume":"175","author":"Krebs","year":"1996","journal-title":"Am J Obstet Gynecol"},{"key":"2023122305010425600_gaad041-B48755959","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1159\/000063690","article-title":"Vasculogenesis, angiogenesis and the molecular organisation of endothelial junctions in the early human placenta","volume":"39","author":"Leach","year":"2002","journal-title":"J Vasc Res"},{"key":"2023122305010425600_gaad041-B24","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1161\/ATVBAHA.119.312653","article-title":"CD146 (cluster of differentiation 146)","volume":"39","author":"Leroyer","year":"2019","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2023122305010425600_gaad041-B25","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1038\/s41422-018-0066-y","article-title":"Single-cell RNA-seq reveals the diversity of trophoblast subtypes and patterns of differentiation in the human placenta","volume":"28","author":"Liu","year":"2018","journal-title":"Cell Res"},{"key":"2023122305010425600_gaad041-B26","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1016\/j.ajpath.2016.12.002","article-title":"Placental stem villus arterial remodeling associated with reduced hydrogen sulfide synthesis contributes to human fetal growth restriction","volume":"187","author":"Lu","year":"2017","journal-title":"Am J Pathol"},{"key":"2023122305010425600_gaad041-B27","first-page":"183","article-title":"Risk of stillbirth, preterm delivery, and fetal growth restriction following exposure in a previous birth: systematic review and meta-analysis","author":"Malacova","year":"2018"},{"key":"2023122305010425600_gaad041-B28","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1053\/plac.2002.0865","article-title":"Fetoplacental angiogenesis during gestation is biphasic, longitudinal and occurs by proliferation and remodelling of vascular endothelial cells","volume":"23","author":"Mayhew","year":"2002","journal-title":"Placenta"},{"key":"2023122305010425600_gaad041-B29","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1111\/j.1479-828X.2007.00778.x","article-title":"Fetal growth restriction and other risk factors for stillbirth in a New Zealand setting","volume":"47","author":"McCowan","year":"2007","journal-title":"Aust N Z J Obstet Gynaecol"},{"key":"2023122305010425600_gaad041-B30","first-page":"282","article-title":"Placental vessel morphometry in growth retardation and increased resistance of the umbilical artery Doppler flow","volume":"9","author":"Mitra","year":"2000","journal-title":"J Matern Fetal Med"},{"key":"2023122305010425600_gaad041-B31","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1007\/s00404-017-4341-9","article-title":"Fetal growth restriction: current knowledge","volume":"295","author":"Nardozza","year":"2017","journal-title":"Arch Gynecol Obstet"},{"key":"2023122305010425600_gaad041-B32","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.bpobgyn.2004.02.003","article-title":"The role of uterine artery Doppler in predicting adverse pregnancy outcome","volume":"18","author":"Papageorghiou","year":"2004","journal-title":"Best Pract Res Clin Obstet Gynaecol"},{"key":"2023122305010425600_gaad041-B33","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12575-016-0040-3","article-title":"Endothelial mesenchymal transition: comparative analysis of different induction methods","volume":"18","author":"Pinto","year":"2016","journal-title":"Biol Proced Online"},{"key":"2023122305010425600_gaad041-B34","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.52004","article-title":"Single cell transcriptional signatures of the human placenta in term and preterm parturition","volume":"8","author":"Pique-Regi","year":"2019","journal-title":"Elife"},{"key":"2023122305010425600_gaad041-B35","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1080\/14767058.2017.1414179","article-title":"CD15 as a marker of fetoplacental endothelial immaturity in IUGR placentas","volume":"32","author":"Ravikumar","year":"2019","journal-title":"J Matern Fetal Neonatal Med"},{"key":"2023122305010425600_gaad041-B36","doi-asserted-by":"crossref","first-page":"6036","DOI":"10.1182\/blood-2010-12-326017","article-title":"Lysophosphatidic acid suppresses endothelial cell CD36 expression and promotes angiogenesis via a PKD-1-dependent signaling pathway","volume":"117","author":"Ren","year":"2011","journal-title":"Blood"},{"key":"2023122305010425600_gaad041-B37","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1161\/CIRCULATIONAHA.113.007469","article-title":"Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension","volume":"129","author":"Ricard","year":"2014","journal-title":"Circulation"},{"key":"2023122305010425600_gaad041-B38","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1055\/s-0031-1275520","article-title":"The early origins of cardiovascular health and disease: who, when, and how","volume":"29","author":"Rueda-Clausen","year":"2011","journal-title":"Semin Reprod Med"},{"key":"2023122305010425600_gaad041-B39","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1002\/dvdy.24589","article-title":"Endothelial-to-mesenchymal transition in cardiovascular diseases: developmental signaling pathways gone awry","volume":"247","author":"S\u00e1nchez-Duffhues","year":"2018","journal-title":"Dev Dyn"},{"key":"2023122305010425600_gaad041-B40","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.stemcr.2018.01.011","article-title":"Meso-endothelial bipotent progenitors from human placenta display distinct molecular and cellular identity","volume":"10","author":"Shafiee","year":"2018","journal-title":"Stem Cell Reports"},{"key":"2023122305010425600_gaad041-B41","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/ki.2015.103","article-title":"Interactions of DPP-4 and integrin \u03b21 influences endothelial-to-mesenchymal transition","volume":"88","author":"Shi","year":"2015","journal-title":"Kidney Int"},{"key":"2023122305010425600_gaad041-B42","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jchemneu.2018.06.001","article-title":"Markers for human brain pericytes and smooth muscle cells","volume":"92","author":"Smyth","year":"2018","journal-title":"J Chem Neuroanat"},{"key":"2023122305010425600_gaad041-B43","doi-asserted-by":"crossref","first-page":"eaau4788","DOI":"10.1126\/sciadv.aau4788","article-title":"A single-cell survey of the human first-trimester placenta and decidua","volume":"4","author":"Suryawanshi","year":"2018","journal-title":"Sci Adv"},{"key":"2023122305010425600_gaad041-B44","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3389\/fcvm.2018.00154","article-title":"It takes two: endothelial-perivascular cell cross-talk in vascular development and disease","volume":"5","author":"Sweeney","year":"2018","journal-title":"Front Cardiovasc Med"},{"key":"2023122305010425600_gaad041-B45","author":"Swietlik","year":"2016"},{"key":"2023122305010425600_gaad041-B46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-46151-6","article-title":"Differences in placental capillary shear stress in fetal growth restriction may affect endothelial cell function and vascular network formation","volume":"9","author":"Tun","year":"2019","journal-title":"Sci Rep"},{"key":"2023122305010425600_gaad041-B47","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1002\/cyto.a.22625","article-title":"FlowSOM: Using self-organizing maps for visualization and interpretation of cytometry data","volume":"87","author":"Van Gassen","year":"2015","journal-title":"Cytometry A"},{"key":"2023122305010425600_gaad041-B48","doi-asserted-by":"crossref","first-page":"3321","DOI":"10.1182\/blood-2010-04-279489","article-title":"The first trimester human placenta is a site for terminal maturation of primitive erythroid cells","volume":"116","author":"Van Handel","year":"2010","journal-title":"Blood"},{"key":"2023122305010425600_gaad041-B49","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s41586-018-0698-6","article-title":"Single-cell reconstruction of the early maternal\u2013fetal interface in humans","volume":"563","author":"Vento-Tormo","year":"2018","journal-title":"Nature"},{"key":"2023122305010425600_gaad041-B50","first-page":"2017","article-title":"Angiogenic sprouting is regulated by endothelial cell expression of Slug","volume":"127","author":"Welch-Reardon","year":"2014","journal-title":"J Cell Sci"},{"key":"2023122305010425600_gaad041-B51","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1053\/plac.2002.0856","article-title":"Placental vessel adaptation during gestation and to high altitude: changes in diameter and perivascular cell coverage","volume":"23","author":"Zhang","year":"2002","journal-title":"Placenta"}],"container-title":["Molecular Human Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/molehr\/advance-article-pdf\/doi\/10.1093\/molehr\/gaad041\/54042072\/gaad041.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/molehr\/article-pdf\/29\/12\/gaad041\/54770654\/gaad041.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/molehr\/article-pdf\/29\/12\/gaad041\/54770654\/gaad041.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,23]],"date-time":"2023-12-23T00:01:52Z","timestamp":1703289712000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/molehr\/article\/doi\/10.1093\/molehr\/gaad041\/7459907"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,29]]},"references-count":52,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2023,11,29]]}},"URL":"https:\/\/doi.org\/10.1093\/molehr\/gaad041","relation":{},"ISSN":["1460-2407"],"issn-type":[{"value":"1460-2407","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,12,1]]},"published":{"date-parts":[[2023,11,29]]},"article-number":"gaad041"}}