{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T14:18:17Z","timestamp":1783606697147,"version":"3.55.0"},"reference-count":38,"publisher":"Bioscientifica","issue":"3","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,10,1]]},"abstract":"<jats:p>While pregnancy is known to be an inflammatory condition, preeclampsia (PE) is associated with higher chemokines and pro-inflammatory cytokines and higher Th1\/Th2 and Th17\/Treg ratios. Since the uteroplacental space can secrete cytokines, including TNF and IL1B, a common assumption is that the proinflammatory immune cell profile of Th1 and Th17 cells dominating over Th2 and Treg cells begins in that space. To date, a possible role for endothelium in this initiation process has not been considered. Nonetheless, recent publications show that endothelium can become immunomodulatory on exposure to TNF and IL1B, and in systemic hypertension, endothelium has been shown to exist as multiple cell subtypes. We have recently shown that uterine artery endothelial cells from late-pregnant sheep (P-UAEC) treated with TNF alone secrete many of the chemokines and cytokines further elevated in PE subjects. Herein, we show that P-UAEC also exist in multiple subtypes with distinct chemokine and cytokine secretory and immunomodulatory properties. The five subtypes are differentially regulated by TNF-alpha (TNF) and IL1-beta (IL1B), which may favor subtype-specific binding and interaction with distinct classes of Th cells, and an altered ability to respond to Th-secreted cytokines (such as IL17 and IL10). Thus, our data demonstrate the possibility that certain endothelial cell subtypes can be pushed to express immunomodulatory proteins by early exposure to increases in TNF or IL1B of immune cell, trophoblast, and decidual origin. This, in turn, begs the question of whether such endothelial changes could contribute to subsequent immune disturbances seen at the time of clinical presentation.<\/jats:p>","DOI":"10.1530\/jme-24-0086","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T09:47:07Z","timestamp":1758880027000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-6","source":"Crossref","is-referenced-by-count":2,"title":["Single-cell analysis of uterine artery endothelial cells reveals cytokine-induced emergence of specific immunomodulatory subtypes: implications for preeclampsia"],"prefix":"10.1530","volume":"75","author":[{"given":"R L","family":"Dahn","sequence":"first","affiliation":[{"name":"Perinatal Research Laboratories, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin\u2013Madison, 7E Unity Point Health-Meriter Hospital 1 , , ,","place":["Madison, Wisconsin, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B M","family":"Lett","sequence":"additional","affiliation":[{"name":"Perinatal Research Laboratories, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin\u2013Madison, 7E Unity Point Health-Meriter Hospital 1 , , ,","place":["Madison, Wisconsin, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0566-6672","authenticated-orcid":true,"given":"L","family":"Clemente","sequence":"additional","affiliation":[{"name":"Perinatal Research Laboratories, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin\u2013Madison, 7E Unity Point Health-Meriter Hospital 1 , , ,","place":["Madison, Wisconsin, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J L","family":"Austin","sequence":"additional","affiliation":[{"name":"Perinatal Research Laboratories, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin\u2013Madison, 7E Unity Point Health-Meriter Hospital 1 , , ,","place":["Madison, Wisconsin, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F X","family":"Yi","sequence":"additional","affiliation":[{"name":"Perinatal Research Laboratories, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin\u2013Madison, 7E Unity Point Health-Meriter Hospital 1 , , ,","place":["Madison, Wisconsin, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D S","family":"Boeldt","sequence":"additional","affiliation":[{"name":"Perinatal Research Laboratories, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin\u2013Madison, 7E Unity Point Health-Meriter Hospital 1 , , ,","place":["Madison, Wisconsin, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A K","family":"Stanic","sequence":"additional","affiliation":[{"name":"Perinatal Research Laboratories, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin\u2013Madison, 7E Unity Point Health-Meriter Hospital 1 , , ,","place":["Madison, Wisconsin, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I M","family":"Ong","sequence":"additional","affiliation":[{"name":"Perinatal Research Laboratories, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin\u2013Madison, 7E Unity Point Health-Meriter Hospital 1 , , ,","place":["Madison, Wisconsin, USA"]},{"name":"Department Biostatistics & Medical Informatics, School Medicine and Public Health, University of Wisconsin\u2013Madison! 2 . , ,","place":["Madison, Wisconsin, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2171-729X","authenticated-orcid":true,"given":"I M","family":"Bird","sequence":"additional","affiliation":[{"name":"Perinatal Research Laboratories, Department of Obstetrics and Gynecology, School Medicine and Public Health, University of Wisconsin\u2013Madison, 7E Unity Point Health-Meriter Hospital 1 , , ,","place":["Madison, Wisconsin, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2025,9,26]]},"reference":[{"key":"2026070811352430900_bib1","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.3390\/cells11162537","article-title":"Roads to Stat3 paved with cadherins","volume":"11","author":"Adan","year":"2022","journal-title":"Cells"},{"key":"2026070811352430900_bib4","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.mce.2019.02.008","article-title":"TNF-alpha inhibits pregnancy-adapted Ca2+ signaling in uterine artery endothelial cells","volume":"488","author":"Ampey","year":"2019","journal-title":"Mol Cell Endocrinol"},{"key":"2026070811352430900_bib5","doi-asserted-by":"crossref","DOI":"10.1016\/j.mce.2021.111368","article-title":"Differential control of uterine artery endothelial monolayer integrity by TNF and VEGF is achieved through multiple mechanisms operating inside and outside the cell \u2013 relevance to preeclampsia","volume":"534","author":"Ampey","year":"2021","journal-title":"Mol Cell Endocrinol"},{"key":"2026070811352430900_bib7","first-page":"1582","article-title":"Hypoxia stimulates cytokine production by villous explants from the human placenta","volume":"82","author":"Benyo","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070811352430900_bib8","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1210\/endo.141.3.7367","article-title":"Pregnancy-dependent changes in cell signaling underlie changes in differential control of vasodilator production in uterine artery endothelial cells","volume":"141","author":"Bird","year":"2000","journal-title":"Endocrinology"},{"key":"2026070811352430900_bib9","doi-asserted-by":"crossref","first-page":"712","DOI":"10.2174\/1570161111311050009","article-title":"Pregnancy, programming and preeclampsia: gap junctions at the nexus of pregnancy-induced adaptation of endothelial function and endothelial adaptive failure in PE","volume":"11","author":"Bird","year":"2013","journal-title":"Curr Vasc Pharmacol"},{"key":"2026070811352430900_bib13","doi-asserted-by":"crossref","first-page":"154","DOI":"10.4049\/jimmunol.2200061","article-title":"Proteogenomic and V(D)J analysis of human decidual T cells highlights unique transcriptional programming and clonal distribution","volume":"211","author":"Chasman","year":"2023","journal-title":"J Immunol"},{"key":"2026070811352430900_bib15","doi-asserted-by":"crossref","first-page":"294","DOI":"10.3389\/fimmu.2018.00294","article-title":"Endothelial to mesenchymal transition represents a key link in the interaction between inflammation and endothelial dysfunction","volume":"9","author":"Cho","year":"2018","journal-title":"Front Immunol"},{"key":"2026070811352430900_bib16","doi-asserted-by":"crossref","DOI":"10.1530\/JME-25-0008","article-title":"TNF but not VEGF induces secretion of multiple chemokines and cytokines by uterine artery endothelial cells \u2013 potential implications for preeclampsia","volume":"75","author":"Clemente","year":"2025","journal-title":"J Mol Endocrinol"},{"key":"2026070811352430900_bib18","doi-asserted-by":"crossref","DOI":"10.1093\/gigascience\/giab096","article-title":"An improved ovine reference genome assembly to facilitate in-depth functional annotation of the sheep genome","volume":"11","author":"Davenport","year":"2022","journal-title":"Gigascience"},{"key":"2026070811352430900_bib19","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.4049\/jimmunol.145.6.1727","article-title":"IFN-gamma enhances endothelial activation induced by tumor necrosis factor but not IL-1","volume":"145","author":"Doukas","year":"1990","journal-title":"J Immunol"},{"key":"2026070811352430900_bib20","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1167\/iovs.18-25068","article-title":"Loss of platelet endothelial cell adhesion molecule-1 (PECAM-1) in the diabetic retina: role of matrix metalloproteinases","volume":"60","author":"Eshaq","year":"2019","journal-title":"Investig Ophthalmol Vis Sci"},{"key":"2026070811352430900_bib21","doi-asserted-by":"crossref","first-page":"346","DOI":"10.2119\/molmed.2013.00035","article-title":"Enhanced inducible costimulator ligand (ICOS-L) expression on dendritic cells in interleukin-10 deficiency and its impact on T-cell subsets in respiratory tract infection","volume":"19","author":"Gao","year":"2013","journal-title":"Mol Med"},{"key":"2026070811352430900_bib22","doi-asserted-by":"crossref","first-page":"3750","DOI":"10.4049\/jimmunol.135.6.3750","article-title":"Antigen presentation by interferon-gamma-treated endothelial cells and fibroblasts: differential ability to function as antigen-presenting cells despite comparable Ia expression","volume":"135","author":"Geppert","year":"1985","journal-title":"J Immunol"},{"key":"2026070811352430900_bib24","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"2026070811352430900_bib25","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/S0002-9440(10)63192-6","article-title":"Secretion of tumor necrosis factor-alpha from human placental tissues induced by hypoxia-reoxygenation causes endothelial cell activation in vitro: a potential mediator of the inflammatory response in preeclampsia","volume":"164","author":"Hung","year":"2004","journal-title":"Am J Pathol Mar"},{"key":"2026070811352430900_bib27","doi-asserted-by":"crossref","first-page":"R693","DOI":"10.1152\/ajpregu.00259.2017","article-title":"Immune regulation of systemic hypertension, pulmonary arterial hypertension, and preeclampsia: shared disease mechanisms and translational opportunities","volume":"313","author":"Jafri","year":"2017","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2026070811352430900_bib28","doi-asserted-by":"crossref","first-page":"4342","DOI":"10.1073\/pnas.92.10.4342","article-title":"CD40 on human endothelial cells: inducibility by cytokines and functional regulation of adhesion molecule expression","volume":"92","author":"Karmann","year":"1995","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026070811352430900_bib30","doi-asserted-by":"crossref","first-page":"3838","DOI":"10.4049\/jimmunol.1300524","article-title":"CagA-dependent downregulation of B7-H2 expression on gastric mucosa and inhibition of Th17 responses during Helicobacter pylori infection","volume":"191","author":"Lina","year":"2013","journal-title":"J Immunol"},{"key":"2026070811352430900_bib32","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/j.placenta.2011.09.015","article-title":"ADAM17 regulates TNF\u03b1 production by placental trophoblasts","volume":"32","author":"Ma","year":"2011","journal-title":"Placenta"},{"key":"2026070811352430900_bib34","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/1756-8722-6-61","article-title":"An evolving new paradigm: endothelial cells \u2013 conditional innate immune cells","volume":"6","author":"Mai","year":"2013","journal-title":"J Hematol Oncol"},{"key":"2026070811352430900_bib36","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1161\/HYPERTENSIONAHA.118.11644","article-title":"Research recommendations from the national institutes of health workshop on predicting, preventing, and treating preeclampsia","volume":"73","author":"Maric-Bilkan","year":"2019","journal-title":"Hypertension"},{"key":"2026070811352430900_bib38","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1161\/CIRCULATIONAHA.115.018912","article-title":"Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries","volume":"134","author":"Mills","year":"2016","journal-title":"Circulation"},{"key":"2026070811352430900_bib41","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3000448","article-title":"The inducible costimulator (ICOS) is critical for the development of human TH17 cells","volume":"2","author":"Paulos","year":"2010","journal-title":"Sci Transl Med"},{"key":"2026070811352430900_bib42","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.3389\/fimmu.2017.01907","article-title":"Antigen presentation by vascular cells","volume":"8","author":"Pober","year":"2017","journal-title":"Front Immunol"},{"key":"2026070811352430900_bib43","doi-asserted-by":"crossref","first-page":"S21","DOI":"10.1053\/plac.2002.0930","article-title":"Pre-eclampsia, the placenta and the maternal systemic inflammatory response \u2013 a review","volume":"24","author":"Redman","year":"2003","journal-title":"Placenta"},{"key":"2026070811352430900_bib44","first-page":"R441","article-title":"Nitric oxide and pregnancy","volume":"272","author":"Sladek","year":"1997","journal-title":"Am J Physiol"},{"key":"2026070811352430900_bib45","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1006\/excr.2001.5256","article-title":"CD40L induces matrix-metalloproteinase-9 but not tissue inhibitor of metalloproteinases-1 in cervical carcinoma cells: imbalance between NF-\u03baB and STAT3 activation","volume":"267","author":"Smola-Hess","year":"2001","journal-title":"Exp Cell Res"},{"key":"2026070811352430900_bib50","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2021.648946","article-title":"IFN\u03b3, and to a lesser extent TNF\u03b1, provokes a sustained endothelial costimulatory phenotype","volume":"12","author":"Valenzuela","year":"2021","journal-title":"Front Immunol"},{"key":"2026070811352430900_bib51","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":"2026070811352430900_bib52","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1182\/blood.V99.2.520","article-title":"Cytokine-inducible CD40 expression in human endothelial cells is mediated by interferon regulatory factor-1","volume":"99","author":"Wagner","year":"2002","journal-title":"Blood"},{"key":"2026070811352430900_bib53","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1067\/mob.2002.119638","article-title":"Endothelial junctional protein redistribution and increased monolayer permeability in human umbilical vein endothelial cells isolated during preeclampsia","volume":"186","author":"Wang","year":"2002","journal-title":"Am J Obstet Gynecol"},{"key":"2026070811352430900_bib54","doi-asserted-by":"crossref","first-page":"2421","DOI":"10.1210\/jc.2003-031707","article-title":"Placental trophoblast-derived factors diminish endothelial barrier function","volume":"89","author":"Wang","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070811352430900_bib55","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1080\/15384047.2020.1842705","article-title":"CXCL6 regulates cell permeability, proliferation, and apoptosis after ischemia-reperfusion injury by modulating Sirt3 expression via AKT\/FOXO3a activation","volume":"22","author":"Wang","year":"2021","journal-title":"Cancer Biol Ther"},{"key":"2026070811352430900_bib58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0008-8749(88)90046-9","article-title":"Effect of interferon-gamma and tumor necrosis factor on the expression of class I and class II major histocompatibility molecules by cultured human umbilical vein endothelial cells","volume":"111","author":"Wedgwood","year":"1988","journal-title":"Cell Immunol"},{"key":"2026070811352430900_bib60","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1084\/jem.182.6.1857","article-title":"Functional interactions of T cells with endothelial cells: the role of CD40L-CD40-mediated signals","volume":"182","author":"Yellin","year":"1995","journal-title":"J Exp Med"},{"key":"2026070811352430900_bib61","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1095\/biolreprod.109.078253","article-title":"Pregnancy enhances sustained Ca2+ bursts and endothelial nitric oxide synthase activation in ovine uterine artery endothelial cells through increased connexin 43 function","volume":"82","author":"Yi","year":"2010","journal-title":"Biol Reprod"},{"key":"2026070811352430900_bib62","doi-asserted-by":"crossref","first-page":"14049","DOI":"10.1038\/ncomms14049","article-title":"Massively parallel digital transcriptional profiling of single cells","volume":"8","author":"Zheng","year":"2017","journal-title":"Nat Commun"}],"container-title":["Journal of Molecular Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jme.bioscientifica.com\/view\/journals\/jme\/75\/3\/JME-24-0086.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/jme.bioscientifica.com\/downloadpdf\/journals\/jme\/75\/3\/JME-24-0086.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/jme\/article-pdf\/doi\/10.1530\/JME-24-0086\/247128\/jme-24-0086.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/jme\/article-pdf\/doi\/10.1530\/JME-24-0086\/247128\/jme-24-0086.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T15:35:31Z","timestamp":1783524931000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/jme\/article\/75\/3\/e240086\/14659\/Single-cell-analysis-of-uterine-artery-endothelial"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,26]]},"references-count":38,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,10,1]]}},"URL":"https:\/\/doi.org\/10.1530\/jme-24-0086","relation":{},"ISSN":["1479-6813","0952-5041"],"issn-type":[{"value":"1479-6813","type":"electronic"},{"value":"0952-5041","type":"print"}],"subject":[],"published":{"date-parts":[[2025,9,26]]},"article-number":"e240086"}}