{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T14:29:48Z","timestamp":1792074588174,"version":"4.4.0"},"reference-count":45,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T00:00:00Z","timestamp":1719878400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32160152"],"award-info":[{"award-number":["32160152"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Alzheimer's disease (AD) is a neurodegenerative disorder with a distinct sex bias. Age\u2010related vascular alterations, a hallmark of AD onset and progression, are consistently associated with sexual dimorphism. Here, we conducted an integrative meta\u2010analysis of 335,803 single\u2010nucleus transcriptomes and 667 bulk transcriptomes from the vascular system in AD and normal aging to address the underlying sex\u2010dependent vascular aging in AD. All vascular cell types in male AD patients exhibited an activated hypoxia response and downstream signaling pathways including angiogenesis. The female AD vasculature is characterized by increased antigen presentation and decreased angiogenesis. We further confirmed that these sex\u2010biased alterations in the cerebral vascular emerged and were primarily determined in the early stages of AD. Sex\u2010stratified analysis of normal vascular aging revealed that angiogenesis and various stress\u2010response genes were downregulated concurrently with female aging. Conversely, the hypoxia response increased steadily in males upon aging. An investigation of upstream driver transcription factors (TFs) revealed that altered communication between estrogen receptor alpha (<jats:italic>ESR1<\/jats:italic>) and hypoxia induced factors during menopause contributes to the inhibition of angiogenesis during normal female vascular aging. Additionally, inhibition of <jats:italic>CREB1<\/jats:italic>, a TF that targets estrogen, is also related to female AD. Overall, our study revealed a distinct cerebral vascular profile in females and males, and revealed novel targets for precision medicine therapy for AD.<\/jats:p>","DOI":"10.1111\/acel.14264","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T12:41:38Z","timestamp":1719924098000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Activation of the hypoxia response in the aging cerebrovasculature protects males against cognitive impairment"],"prefix":"10.1111","volume":"23","author":[{"given":"Peihu","family":"Li","sequence":"first","affiliation":[{"name":"College of Biomedical Information and Engineering Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoman","family":"Bi","sequence":"additional","affiliation":[{"name":"College of Biomedical Information and Engineering Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dahua","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Biomedical Information and Engineering Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Meng","sequence":"additional","affiliation":[{"name":"Wannan Medical College  Wuhu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yucheng","family":"Xia","sequence":"additional","affiliation":[{"name":"College of Biomedical Information and Engineering Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiale","family":"Cai","sequence":"additional","affiliation":[{"name":"College of Biomedical Information and Engineering Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Shen","sequence":"additional","affiliation":[{"name":"College of Biomedical Information and Engineering Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Biomedical Information and Engineering Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiazhu","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Biomedical Information and Engineering Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamei","family":"Yin","sequence":"additional","affiliation":[{"name":"College of Biomedical Information and Engineering Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Biomedical Information and Engineering Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deng","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Faculty of Science The Chinese University of Hong Kong  Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4928-6922","authenticated-orcid":false,"given":"Kongning","family":"Li","sequence":"additional","affiliation":[{"name":"College of Biomedical Information and Engineering Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University  Haikou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,7,2]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13016"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.118020"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(16)30029-1"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2021.101343"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2023.1105620"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2010.03.003"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2007.03.001"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-005-1413-7"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00262.2020"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000912"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.2174\/1567205013666160229112725"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12897"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-018-1031-y"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-11-80"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharep.2015.07.006"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2653"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2007.09.019"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(96)01000-4"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.319902"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2018.08.008"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.101769"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000271090.28148.24"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2006-1394"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2008762117"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2009.07.014"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci12111428"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1300813"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-2244"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21256"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.04.008"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06802-1"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2006.03.006"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.49.6.1491"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yhbeh.2018.09.005"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-023-01334-3"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00050.2017"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0222-06.2006"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.107.158014"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-023-02987-4"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2006.04.020"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04369-3"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1422015112"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-020-00565-5"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2009.03.002"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1159\/000088448"}],"container-title":["Aging Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.14264","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T12:16:31Z","timestamp":1728562591000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/acel.14264"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,2]]},"references-count":45,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2024,10]]}},"alternative-id":["10.1111\/acel.14264"],"URL":"https:\/\/doi.org\/10.1111\/acel.14264","archive":["Portico"],"relation":{},"ISSN":["1474-9718","1474-9726"],"issn-type":[{"value":"1474-9718","type":"print"},{"value":"1474-9726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,2]]},"assertion":[{"value":"2024-01-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e14264"}}