{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:21:42Z","timestamp":1787016102475,"version":"build-2736575974"},"reference-count":56,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T00:00:00Z","timestamp":1733702400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UL1TR002373"],"award-info":[{"award-number":["UL1TR002373"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Preeclampsia (PE) is a hypertensive disorder during human pregnancy. Aryl hydrocarbon receptor (AhR) is a ligand\u2010activated transcription factor. Exogenous and endogenous AhR ligands can induce hypertension in male rats and mice. Herein, using rats as a model, we tested the hypothesis that over\u2010regulation of endogenous AhR ligands during pregnancy impairs vascular functions by disrupting the transcriptome in the placenta, contributing to the development of PE. Pregnant rats were injected daily with an endogenous AhR ligand, 2\u2010(1\u2032\n                      <jats:italic>H<\/jats:italic>\n                      \u2010indole\u20103\u2032\u2010carbonyl)\u2010thiazole\u20104\u2010carboxylic acid methyl ester (ITE), from gestational day (GD) 10 to 19. Maternal mean blood pressure was measured on GD16\u201320. Proteinuria and uteroplacental blood flow were monitored on GD20. Placentas collected on GD20 were used to determine changes in vascular density and transcriptome. Compared with the vehicle control, ITE elevated maternal mean blood pressure by 22% and 16% on GD16 and 17, respectively. ITE increased proteinuria by 50% and decreased uteroplacental blood flow by 26%. ITE reduced the placental vascular density by 18%. RNA sequencing analysis revealed that ITE induced 1316 and 2020 differentially expressed genes (DEGs) in female and male placentas, respectively. These DEGs were enriched in pathways relevant to heart diseases, vascular functions and inflammation. Bioinformatics analysis also predicted that ITE altered immune cell infiltration in placentas depending on fetal sex. These data suggest that over\u2010regulation of endogenous AhR ligands may lead to PE with impaired vascular functions and disrupted fetal sex\u2010specific transcriptomes and immune cell infiltration in placentas. These AhR ligand\u2010induced DEGs and pathways may represent promising therapeutic targets for PE\u2010induced cardiovascular dysfunctions.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16443-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>An endogenous AhR ligand (ITE) elevated maternal blood pressure and proteinuria in pregnant rats, and decreased uteroplacental blood flow and fetal and placental growth, all of which are hallmarks of preeclampsia.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>ITE reduced vascular density and altered immune cell distribution in rat placentas.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>ITE dysregulated transcriptomes in rat placentas in a fetal sex\u2010specific manner. These ITE\u2010dysregulated genes and pathways are highly relevant to diseases of heart, vascular functions and inflammatory responses.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp287503","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T12:13:42Z","timestamp":1733746422000},"page":"579-594","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["An endogenous aryl hydrocarbon receptor ligand induces preeclampsia\u2010like phenotypes in rats"],"prefix":"10.1113","volume":"603","author":[{"given":"Ying\u2010Jie","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Wisconsin\u2010Madison Madison WI USA"},{"name":"Department of Rheumatology, Qilu Hospital, Cheeloo College of Medicine Shandong University Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3349-9069","authenticated-orcid":false,"given":"Chi","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Animal and Comparative Biomedical Sciences University of Arizona Tucson AZ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si\u2010Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Wisconsin\u2010Madison Madison WI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0835-3292","authenticated-orcid":false,"given":"Jay S.","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences University of Wisconsin\u2010Madison Madison WI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui\u2010Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Wisconsin\u2010Madison Madison WI USA"},{"name":"Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine Shandong University Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Lei","sequence":"additional","affiliation":[{"name":"Cardiovascular Medicine Center Affiliated Hospital of Guangdong Medical University Zhanjiang Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology Tongji University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sathish","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Wisconsin\u2010Madison Madison WI USA"},{"name":"Department of Comparative Biosciences University of Wisconsin\u2010Madison Madison WI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2224-2372","authenticated-orcid":false,"given":"Jing","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Wisconsin\u2010Madison Madison WI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,9]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2011.06.011"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.114.04521"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0143-4004(05)80643-5"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.25497"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfr218"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202201159"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00298"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9378(82)90474-4"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02426"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.115.06946"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.12.012"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2006.02.008"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24043240"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2008.09.037"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2008.10.030"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1385\/CT:5:2:215"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1369\/jhc.2010.955955"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0030-1253453"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1258\/0023677041958945"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/FM9.0000000000000132"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2017.09.010"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2015.08.003"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1369\/0022155414558063"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioaa128"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.107.100586"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2005.07.005"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2023899118"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.5RU1120-787RR"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.119.13429"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1507\/endocrj.51.569"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-2115(03)00169-6"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12884-019-2383-7"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx7001965"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP277643"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1080\/01902148.2017.1367868"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.3109\/10408449309105013"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.52004"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0016-5"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1530\/rep.1.00294"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.313276"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.120.14781"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0125-8"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/jp.2011.101"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2022.03.002"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.232562899"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfr150"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032713-120245"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0404379101"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2013.06.026"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0086549"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2009.10.889"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.4103\/0975-3583.83033"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43032-021-00759-0"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP284746"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.118.12569"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2017-00849"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP287503","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T11:56:33Z","timestamp":1737028593000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP287503"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,9]]},"references-count":56,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,1]]}},"alternative-id":["10.1113\/JP287503"],"URL":"https:\/\/doi.org\/10.1113\/jp287503","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,9]]},"assertion":[{"value":"2024-08-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}