{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T01:20:02Z","timestamp":1780708802080,"version":"3.54.1"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>\n              Postnatal angiogenesis is critical in vascular homeostasis and repair. m\n              <jats:sup>6<\/jats:sup>\n              A (N6-methyladenosine) RNA methylation is emerging as a new layer for fine-tuning gene expression. Although the contribution of the m\n              <jats:sup>6<\/jats:sup>\n              A-catalyzing enzyme, METTL3 (methyltransferase-like 3), in cancer biology has been described, its role in endothelial cell (EC) function, particularly during angiogenesis, remains unclear.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results:<\/jats:title>\n            <jats:p>\n              To characterize the relevance of METTL3 in angiogenesis regulation, we performed gain- and loss-of-function studies in vitro. We demonstrated that depletion of METTL3 in ECs reduced the level of m\n              <jats:sup>6<\/jats:sup>\n              A and impaired EC function, whereas adenovirus-mediated METTL3 overexpression increased angiogenesis. Mechanistically, we showed that METTL3 depletion in ECs decreased mature angiogenic microRNAs let-7e-5p and the miR-17-92 cluster, and increased the expression of their common target, Tsp1 (thrombospondin 1). Conversely,\n              <jats:italic>Ad.METTL3<\/jats:italic>\n              increased the expression of let-7e-5p and miR-17-92 cluster and reduced protein levels of Tsp1 in ECs. Moreover, overexpression of let-7e-5p and miR-18a-5p restored the angiogenic potential of METTL3-depleted ECs. We corroborated our data in vivo employing 3 mouse models. When tested in an in vivo Matrigel plug assay, METTL3-depleted ECs had diminished ability to vascularize the plug, whereas overexpression of METTL3 promoted angiogenesis. Local\n              <jats:italic>Ad.METTL3<\/jats:italic>\n              gene transfer increased postischemic neovascularization in mice with either unilateral limb ischemia or myocardial infarction.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              METTL3 regulates m\n              <jats:sup>6<\/jats:sup>\n              A RNA methylation in ECs. Endogenous METTL3 is essential for EC function and angiogenesis, potentially through influencing let-7e and miR-17-92 cluster processing. Thus, the therapeutic modulation of METTL3 should be considered as a new approach for controlling angiogenic responses in the clinical setting.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.121.316180","type":"journal-article","created":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T09:02:24Z","timestamp":1619686944000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":50,"title":["METTL3 Regulates Angiogenesis by Modulating let-7e-5p and miRNA-18a-5p Expression in Endothelial Cells"],"prefix":"10.1161","volume":"41","author":[{"given":"Ar\u00e1nzazu","family":"Chamorro-Jorganes","sequence":"first","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, United Kingdom (A.C.-J., W.K.S., M.A., I.R.-P., C.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walid K.","family":"Sweaad","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, United Kingdom (A.C.-J., W.K.S., M.A., I.R.-P., C.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5419-7935","authenticated-orcid":true,"given":"Rajesh","family":"Katare","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Department of Physiology HeartOtago, University of Otago, Dunedin, New Zealand (R.K., D.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Besnier","sequence":"additional","affiliation":[{"name":"Bristol Heart Institute, University of Bristol, United Kingdom (M.B., G.S.-N.)."},{"name":"Kolling Institute, Northern Clinical School, Faculty of Medicine and Health, University of Sydney, NSW, Australia (M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Anwar","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, United Kingdom (A.C.-J., W.K.S., M.A., I.R.-P., C.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Beazley-Long","sequence":"additional","affiliation":[{"name":"Biodiscovery Institute, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, United Kingdom (N.B.-L., A.A.R., A.V.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graciela","family":"Sala-Newby","sequence":"additional","affiliation":[{"name":"Bristol Heart Institute, University of Bristol, United Kingdom (M.B., G.S.-N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I\u00f1igo","family":"Ruiz-Polo","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, United Kingdom (A.C.-J., W.K.S., M.A., I.R.-P., C.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhananjie","family":"Chandrasekera","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Department of Physiology HeartOtago, University of Otago, Dunedin, New Zealand (R.K., D.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison A.","family":"Ritchie","sequence":"additional","affiliation":[{"name":"Biodiscovery Institute, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, United Kingdom (N.B.-L., A.A.R., A.V.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8225-5159","authenticated-orcid":true,"given":"Andrew V.","family":"Benest","sequence":"additional","affiliation":[{"name":"Biodiscovery Institute, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, United Kingdom (N.B.-L., A.A.R., A.V.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2392-0702","authenticated-orcid":true,"given":"Costanza","family":"Emanueli","sequence":"additional","affiliation":[{"name":"National Heart and Lung 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