{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T22:44:13Z","timestamp":1792017853471,"version":"4.4.0"},"reference-count":68,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T00:00:00Z","timestamp":1622764800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01EB022376"],"award-info":[{"award-number":["R01EB022376"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RM1HG009490"],"award-info":[{"award-number":["RM1HG009490"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01AI142756"],"award-info":[{"award-number":["U01AI142756"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UG3AI1505101"],"award-info":[{"award-number":["UG3AI1505101"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000070","name":"National Institute of Biomedical Imaging and Bioengineering","doi-asserted-by":"publisher","award":["P41 EB023833"],"award-info":[{"award-number":["P41 EB023833"]}],"id":[{"id":"10.13039\/100000070","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R36AG070573"],"award-info":[{"award-number":["R36AG070573"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL126784"],"award-info":[{"award-number":["R01HL126784"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL138252"],"award-info":[{"award-number":["R01HL138252"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Hutchinson\u2013Gilford progeria syndrome (HGPS) is a rare genetic disorder with features of accelerated aging. The majority of HGPS cases are caused by a\n                    <jats:italic>de novo<\/jats:italic>\n                    point mutation in the\n                    <jats:italic>LMNA<\/jats:italic>\n                    gene (c.1824C&gt;T; p.G608G) resulting in progerin, a toxic lamin A protein variant. Children with HGPS typically die from coronary artery diseases or strokes at an average age of 14.6\u00a0years. Endothelial dysfunction is a known driver of cardiovascular pathogenesis; however, it is currently unknown how progerin antagonizes normal angiogenic function in HGPS. Here, we use human iPSC\u2010derived endothelial cell (iPSC\u2010EC) models to study angiogenesis in HGPS. We cultured normal and HGPS iPSC\u2010ECs under both static and fluidic culture conditions. HGPS iPSC\u2010ECs show reduced endothelial nitric oxide synthase (eNOS) expression and activity compared with normal controls and concomitant decreases in intracellular nitric oxide (NO) level, which result in deficits in capillary\u2010like microvascular network formation. Furthermore, the expression of matrix metalloproteinase 9 (MMP\u20109) was reduced in HGPS iPSC\u2010ECs, while the expression of tissue inhibitor metalloproteinases 1 and 2 (TIMP1 and TIMP2) was upregulated relative to healthy controls. Finally, we used an adenine base editor (ABE7.10max\u2010VRQR) to correct the pathogenic c.1824C&gt;T allele in HGPS iPSC\u2010ECs. Remarkably, ABE7.10max\u2010VRQR correction of the HGPS mutation significantly reduced progerin expression to a basal level, rescued nuclear blebbing, increased intracellular NO level, normalized the misregulated TIMPs, and restored angiogenic competence in HGPS iPSC\u2010ECs. Together, these results provide molecular insights of endothelial dysfunction in HGPS and suggest that ABE could be a promising therapeutic approach for correcting HGPS\u2010related cardiovascular phenotypes.\n                  <\/jats:p>","DOI":"10.1111\/acel.13388","type":"journal-article","created":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T12:08:18Z","timestamp":1622808498000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Mechanisms of angiogenic incompetence in Hutchinson\u2013Gilford progeria via downregulation of endothelial NOS"],"prefix":"10.1111","volume":"20","author":[{"given":"Yantenew G.","family":"Gete","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics University of Maryland College Park MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke W.","family":"Koblan","sequence":"additional","affiliation":[{"name":"Merkin Institute of Transformative Technologies in Healthcare Broad Institute of Harvard and MIT Cambridge MA USA"},{"name":"Department of Chemistry and Chemical Biology Harvard University Cambridge MA USA"},{"name":"Howard Hughes Medical Institute Harvard University Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojing","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics University of Maryland College Park MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mason","family":"Trappio","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics University of Maryland College Park MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhushan","family":"Mahadik","sequence":"additional","affiliation":[{"name":"Fischell Department of Bioengineering University of Maryland College Park MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Fisher","sequence":"additional","affiliation":[{"name":"Fischell Department of Bioengineering University of Maryland College Park MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Liu","sequence":"additional","affiliation":[{"name":"Merkin Institute of Transformative Technologies in Healthcare Broad Institute of Harvard and MIT Cambridge MA USA"},{"name":"Department of Chemistry and Chemical Biology Harvard University Cambridge MA USA"},{"name":"Howard Hughes Medical Institute Harvard University Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5806-2939","authenticated-orcid":false,"given":"Kan","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics University of Maryland College Park MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,6,4]]},"reference":[{"issue":"5","key":"e_1_2_9_2_1","first-page":"4417","article-title":"Hutchinson\u2010Gilford Progeria syndrome: A premature aging disease","volume":"55","author":"Ahmed M. 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