{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T10:15:08Z","timestamp":1792145708070,"version":"4.4.0"},"reference-count":62,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T00:00:00Z","timestamp":1619827200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Post\u2010ischemic angiogenesis is critical for blood flow recovery and ischemic tissue repair. N6\u2010methyladenosine (m6A) plays essential roles in numerous biological processes. However, the impact and connected mechanism of m6A on post\u2010ischemic angiogenesis are not fully understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>AlkB homolog 5 (ALKBH5) was screened out among several methyltransferases and demethylases involved in dynamic m6A regulation. Cardiac microvascular endothelial cells (CMECs) angiogenesis and WNT family member 5A (WNT5A) stability were analyzed upon ALKBH5 overexpression with adenovirus or knockdown with small interfering RNAs in vitro. The blood flow recovery, capillary, and small artery densities were evaluated in adeno\u2010associated virus (AAV)\u2010ALKBH5 overexpression or ALKBH5 knockout (KO) mice in a hind\u2010limb ischemia model. The same experiments were conducted to explore the translational value of transient silencing of ALKBH5 with adenovirus.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ALKBH5 was significantly upregulated in hypoxic CMECs and led to a global decrease of m6A level. ALKBH5 overexpression further reduced m6A level in normoxic and hypoxic CMECs, impaired proliferation, migration, and tube formation only in hypoxic CMECs. Conversely, ALKBH5 knockdown preserved m6A levels and promoted angiogenic phenotypes in hypoxic but not in normoxic CMECs. Mechanistically, ALKBH5 regulated WNT5A expression through post\u2010transcriptional mRNA modulation in an m6A\u2010dependent manner, which decreased its stability and subsequently impeded angiogenesis in hypoxic CMECs. Furthermore, ALKBH5 overexpression hindered blood flow recovery and reduced CD31 and alpha\u2010smooth muscle actin expression in hind\u2010limb ischemia mice. As expected, ALKBH5\u2010KO mice exhibited improved blood flow recovery, increased capillary, and small artery densities after hind\u2010limb ischemia, and similar beneficial effects were observed in mice with transient adenoviral\n                      <jats:italic>ALKBH5<\/jats:italic>\n                      gene silencing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We demonstrate that ALKBH5 is a negative regulator of post\u2010ischemic angiogenesis via post\u2010transcriptional modulation and destabilization of\n                      <jats:italic>WNT5A<\/jats:italic>\n                      mRNA in an m6A\u2010dependent manner. Targeting ALKBH5 may be a potential therapeutic option for ischemic diseases, including peripheral artery disease.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.402","type":"journal-article","created":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T05:52:02Z","timestamp":1619848322000},"source":"Crossref","is-referenced-by-count":139,"title":["Loss of m6A demethylase ALKBH5 promotes post\u2010ischemic angiogenesis via post\u2010transcriptional stabilization of WNT5A"],"prefix":"10.1002","volume":"11","author":[{"given":"Yongchao","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"Institute of Biomedical Sciences Fudan University  Shanghai China"},{"name":"NHC Key Laboratory of Viral Heart Diseases  Shanghai China"},{"name":"Key Laboratory of Viral Heart Diseases Chinese Academy of Medical Sciences  Shanghai China"},{"name":"Department of Cardiology Affiliated Hospital of Zunyi Medical University  Zunyi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"Institute of Biomedical Sciences Fudan University  Shanghai China"},{"name":"NHC Key Laboratory of Viral Heart Diseases  Shanghai China"},{"name":"Key Laboratory of Viral Heart Diseases Chinese Academy of Medical Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolei","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"Institute of Biomedical Sciences Fudan University  Shanghai China"},{"name":"NHC Key Laboratory of Viral Heart Diseases  Shanghai China"},{"name":"Key Laboratory of Viral Heart Diseases Chinese Academy of Medical Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"Institute of Biomedical Sciences Fudan University  Shanghai China"},{"name":"NHC Key Laboratory of Viral Heart Diseases  Shanghai China"},{"name":"Key Laboratory of Viral Heart Diseases Chinese Academy of Medical Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lebing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Wenzhou Medicial University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingqiu","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"Institute of Biomedical Sciences Fudan University  Shanghai China"},{"name":"NHC Key Laboratory of Viral Heart Diseases  Shanghai China"},{"name":"Key Laboratory of Viral Heart Diseases Chinese Academy of Medical Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beijian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"Institute of Biomedical Sciences Fudan University  Shanghai China"},{"name":"NHC Key Laboratory of Viral Heart Diseases  Shanghai China"},{"name":"Key Laboratory of Viral Heart Diseases Chinese Academy of Medical Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuhai","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"Institute of Biomedical Sciences Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaofu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"Institute of Biomedical Sciences Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Cardiology Affiliated Hospital of Zunyi Medical University  Zunyi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"Institute of Biomedical Sciences Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aijun","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"Institute of Biomedical Sciences Fudan University  Shanghai China"},{"name":"NHC Key Laboratory of Viral Heart Diseases  Shanghai China"},{"name":"Key Laboratory of Viral Heart Diseases Chinese Academy of Medical Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9360-7332","authenticated-orcid":false,"given":"Junbo","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases  Shanghai China"},{"name":"Institute of Biomedical Sciences Fudan University  Shanghai China"},{"name":"NHC Key Laboratory of Viral Heart Diseases  Shanghai China"},{"name":"Key Laboratory of Viral Heart Diseases Chinese Academy of Medical Sciences  Shanghai China"},{"name":"Department of Cardiology Affiliated Hospital of Zunyi Medical University  Zunyi China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,5]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1067\/mhj.2002.122871"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61682-2"},{"key":"e_1_2_12_4_1","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1007\/s11936-016-0464-8","article-title":"Medical therapy in peripheral artery disease and critical limb ischemia","volume":"18","author":"Foley T","year":"2016","journal-title":"Curr Treat Options Cardiovasc Med"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-017-4488-8"},{"key":"e_1_2_12_6_1","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/s003950050059","article-title":"Effect of basic fibroblast growth factor on angiogenesis in the infarcted porcine heart","volume":"93","author":"Watanabe E","year":"1998","journal-title":"Basic Res Cardiol"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-005-0581-0"},{"key":"e_1_2_12_8_1","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1007\/s00395-020-0808-0","article-title":"Secreted frizzled\u2010related protein 2, a novel mechanism to induce myocardial ischemic protection through angiogenesis","volume":"115","author":"Vatner D","year":"2020","journal-title":"Basic Res Cardiol"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200105243442108"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.200386"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10144"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2006.12.037"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.966408"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.033092"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.001383"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-14076-3"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.003"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(77)90110-3"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0168-5"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.05.014"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.05.048"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12626"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.033794"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.036146"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2019.1586246"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2019103181"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-020-01714-8"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.07.022"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.13572"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2021.119239"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/FJC.0000000000000967"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.115.306012"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1432"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2014.3"},{"key":"e_1_2_12_35_1","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.15252\/embr.201744940","article-title":"NHuman METTL16 is a N6\u2010methyladenosine (m6A) methyltransferase that targets pre\u2010mRNAs and various non\u2010coding RNAs","volume":"18","author":"Ward A","year":"2017","journal-title":"Embo Rep"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.687"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.10.015"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0016210"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-018-0040-8"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.10.166"},{"key":"e_1_2_12_41_1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1080\/08977190701272933","article-title":"Wnt1 and Wnt5a affect endothelial proliferation and capillary length; Wnt2 does not","volume":"25","author":"Goodwin AM","year":"2009","journal-title":"Growth Factors"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.223750"},{"key":"e_1_2_12_43_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/832562","article-title":"Overexpression of Wnt5a promotes angiogenesis in NSCLC","volume":"2014","author":"Yao L","year":"2014","journal-title":"Biomed Res Int"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00776.2016"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.045"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.132"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1080\/15476286.2016.1267096"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-020-01239-w"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-020-01158-w"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2014.151"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1226"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2006.tb00290.x"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.009407"},{"key":"e_1_2_12_54_1","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1161\/01.CIR.0000093398.16124.29","article-title":"Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase ii randomized, double\u2010blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication","volume":"108","author":"Rajagopalan S","year":"2004","journal-title":"Circulation"},{"key":"e_1_2_12_55_1","first-page":"D11741","article-title":"Growth factors for angiogenesis in peripheral arterial disease","volume":"6","author":"Gorenoi V","year":"2017","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_12_56_1","doi-asserted-by":"crossref","first-page":"287","DOI":"10.14336\/AD.2016.0920","article-title":"The soluble VEGF receptor sFlt\u20101 contributes to impaired neovascularization in aged mice","volume":"8","author":"Zhao G","year":"2017","journal-title":"Aging Dis"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3703"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.309516"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E06-04-0320"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.10.166"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.1186\/2045-824X-4-13"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mju036"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2017.06.017"}],"container-title":["Clinical and Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.402","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ctm2.402","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.402","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,2]],"date-time":"2023-09-02T01:18:04Z","timestamp":1693617484000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ctm2.402"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5]]},"references-count":62,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021,5]]}},"alternative-id":["10.1002\/ctm2.402"],"URL":"https:\/\/doi.org\/10.1002\/ctm2.402","archive":["Portico"],"relation":{},"ISSN":["2001-1326","2001-1326"],"issn-type":[{"value":"2001-1326","type":"print"},{"value":"2001-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5]]},"article-number":"e402"}}