{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T07:03:17Z","timestamp":1781766197137,"version":"3.54.5"},"reference-count":61,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T00:00:00Z","timestamp":1654041600000},"content-version":"vor","delay-in-days":151,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002865","name":"Chongqing Municipal Science and Technology Bureau","doi-asserted-by":"publisher","award":["cstc2021ycjh-bgzxm0192"],"award-info":[{"award-number":["cstc2021ycjh-bgzxm0192"]}],"id":[{"id":"10.13039\/501100002865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002865","name":"Chongqing Municipal Science and Technology Bureau","doi-asserted-by":"publisher","award":["cstc2019jcyj-msxmX0856"],"award-info":[{"award-number":["cstc2019jcyj-msxmX0856"]}],"id":[{"id":"10.13039\/501100002865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171662"],"award-info":[{"award-number":["82171662"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U21A20346"],"award-info":[{"award-number":["U21A20346"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82001580"],"award-info":[{"award-number":["82001580"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81871189"],"award-info":[{"award-number":["81871189"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Oxidative Medicine and Cellular Longevity"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:p><jats:italic>Background<\/jats:italic>. Preeclampsia (PE) is associated with insufficient placental perfusion attributed to maldevelopment of the placental vasculature. Reactive oxygen species (ROS) are implicated in angiogenesis, but their regulatory effects and mechanisms in placental vascular development remain unclear. <jats:italic>Methods<\/jats:italic>. Placental oxidative stress was determined throughout gestation by measuring 4\u2010hydroxynonenal (4HNE) and malondialdehyde (MDA). The antioxidant MitoQ was administered to pregnant mice from GDs 7.5 to 11.5; placental morphology and angiogenesis pathways were examined on GDs 11.5 and 18.5. Moreover, we established a mouse mFlt\u20101\u2010induced PE model and assessed blood pressure, urine protein levels, and placental vascular development on GDs 11.5 and 18.5. Human umbilical vein endothelial cells (HUVECs) were treated with various H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> concentrations to evaluate cell viability, intracellular ROS levels, and tube formation capability. MitoQ, an AKT inhibitor and an ERK1\/2 inhibitor were applied to validate the ROS\u2010mediated mechanism regulating placental angiogenesis. <jats:italic>Results<\/jats:italic>. First\u2010trimester placentas presented significantly higher MDA and 4HNE levels. MitoQ significantly reduced the blood vessel density and angiogenesis pathway activity in the placenta on GDs 11.5 and 18.5. Serum sFlt\u20101 levels were elevated, and we observed poor placental angiogenesis and PE\u2010like symptoms in cases with mFlt\u20101 overexpression. Moderate H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> treatment promoted HUVEC proliferation and angiogenesis, whereas these improvements were abolished by MitoQ, AKT inhibitor, or ERK1\/2 inhibitor treatment. <jats:italic>Conclusions<\/jats:italic>. Moderate ROS levels are essential for placental angiogenesis; diminishing ROS with potent antioxidants during placentation decreases placental angiogenesis and increases PE risk. Therefore, antioxidant therapy should be considered carefully for normal pregnant women during early gestation.<\/jats:p>","DOI":"10.1155\/2022\/4290922","type":"journal-article","created":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T04:10:39Z","timestamp":1654143039000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Reactive Oxygen Species are Essential for Placental Angiogenesis During Early Gestation"],"prefix":"10.1155","volume":"2022","author":[{"given":"Yike","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huili","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6480-1147","authenticated-orcid":false,"given":"Yong","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4911-7942","authenticated-orcid":false,"given":"Hongbo","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip N.","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0828-2674","authenticated-orcid":false,"given":"Chao","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,6]]},"reference":[{"key":"e_1_2_10_1_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00040.2011"},{"key":"e_1_2_10_2_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006585"},{"key":"e_1_2_10_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/1746-1596-5-24"},{"key":"e_1_2_10_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/jclinpath-2011-200092"},{"key":"e_1_2_10_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep35536"},{"key":"e_1_2_10_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7985020"},{"key":"e_1_2_10_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119387"},{"key":"e_1_2_10_8_2","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/781632"},{"key":"e_1_2_10_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dem143"},{"key":"e_1_2_10_10_2","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2020.610544"},{"key":"e_1_2_10_11_2","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/814543"},{"key":"e_1_2_10_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7580.2008.00978.x"},{"key":"e_1_2_10_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00418-004-0677-x"},{"key":"e_1_2_10_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000242927.24428.25"},{"key":"e_1_2_10_15_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1474-9728.2002.00015.x"},{"key":"e_1_2_10_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preghy.2017.01.004"},{"key":"e_1_2_10_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.118.11290"},{"key":"e_1_2_10_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2017.12.030"},{"key":"e_1_2_10_19_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.01141"},{"key":"e_1_2_10_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.numecd.2018.06.002"},{"key":"e_1_2_10_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD004227.pub3"},{"key":"e_1_2_10_22_2","first-page":"2548","article-title":"Effect of antioxidants on amelioration of high-risk factors inducing hypertensive disorders in pregnancy","volume":"123","author":"Lin J. H.","year":"2010","journal-title":"Chinese Medical Journal"},{"key":"e_1_2_10_23_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0908056"},{"key":"e_1_2_10_24_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2019.7891"},{"key":"e_1_2_10_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-019-0119-6"},{"key":"e_1_2_10_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10815-020-01750-5"},{"key":"e_1_2_10_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13417"},{"key":"e_1_2_10_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13491"},{"key":"e_1_2_10_29_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2013.5236"},{"key":"e_1_2_10_30_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2016.6747"},{"key":"e_1_2_10_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05249"},{"key":"e_1_2_10_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/9781444393927.ch5"},{"key":"e_1_2_10_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.115.06946"},{"key":"e_1_2_10_34_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells9081849"},{"key":"e_1_2_10_35_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00346.2016"},{"key":"e_1_2_10_36_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.115.06223"},{"key":"e_1_2_10_37_2","doi-asserted-by":"publisher","DOI":"10.1177\/1933719114549857"},{"key":"e_1_2_10_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2005.02.013"},{"key":"e_1_2_10_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-50417-4"},{"key":"e_1_2_10_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2003.11.011"},{"key":"e_1_2_10_41_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aam5711"},{"key":"e_1_2_10_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2397"},{"key":"e_1_2_10_43_2","doi-asserted-by":"publisher","DOI":"10.1023\/B:MCBI.0000044378.09409.b5"},{"key":"e_1_2_10_44_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom9110735"},{"key":"e_1_2_10_45_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0110867"},{"key":"e_1_2_10_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2006.12.024"},{"key":"e_1_2_10_47_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0707330"},{"key":"e_1_2_10_48_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.113.000159"},{"key":"e_1_2_10_49_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20215425"},{"key":"e_1_2_10_50_2","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13009"},{"key":"e_1_2_10_51_2","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2016.5235"},{"key":"e_1_2_10_52_2","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/3181759"},{"key":"e_1_2_10_53_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.10119"},{"key":"e_1_2_10_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2016.08.015"},{"key":"e_1_2_10_55_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-016-0539-4"},{"key":"e_1_2_10_56_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12015-006-0015-x"},{"key":"e_1_2_10_57_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-018-1021-z"},{"key":"e_1_2_10_58_2","first-page":"385","article-title":"Vascular permeability factor, tumor angiogenesis and stroma generation","volume":"14","author":"Senger D. R.","year":"1994","journal-title":"Invasion & Metastasis"},{"key":"e_1_2_10_59_2","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/2467940"},{"key":"e_1_2_10_60_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-12734-3_5"},{"key":"e_1_2_10_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2017.06.007"}],"container-title":["Oxidative Medicine and Cellular Longevity"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/downloads.hindawi.com\/journals\/omcl\/2022\/4290922.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/omcl\/2022\/4290922.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/2022\/4290922","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T01:48:18Z","timestamp":1748915298000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1155\/2022\/4290922"}},"subtitle":[],"editor":[{"given":"Demetrios","family":"Kouretas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,1]]},"references-count":61,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,1]]}},"alternative-id":["10.1155\/2022\/4290922"],"URL":"https:\/\/doi.org\/10.1155\/2022\/4290922","archive":["Portico"],"relation":{},"ISSN":["1942-0900","1942-0994"],"issn-type":[{"value":"1942-0900","type":"print"},{"value":"1942-0994","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1]]},"assertion":[{"value":"2021-12-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-06-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"4290922"}}