{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T03:31:46Z","timestamp":1778038306138,"version":"3.51.4"},"reference-count":16,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"16","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2023,8,15]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Peripheral arterial disease and critical limb ischemia are cardiovascular complications associated with vascular insufficiency, oxidative metabolic dysfunction, and myopathy in the limbs. Estrogen\u2010related receptor gamma (ERR\u03b3) has emerged as a dual regulator of paracrine angiogenesis and oxidative metabolism through transgenic mouse studies. Here our objective was to investigate whether postischemic intramuscular targeting of ERR\u03b3 via gene therapy promotes ischemic recovery in a preclinical model of peripheral arterial disease\/critical limb ischemia.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Adeno\u2010associated virus 9 (AAV9)\n              <jats:italic>Esrrg<\/jats:italic>\n              gene delivery vector was developed and first tested via intramuscular injection in murine skeletal muscle. AAV9\u2010Esrrg robustly increased ERR\u03b3 protein expression, induced angiogenic and oxidative genes, and\u00a0boosted capillary density and succinate dehydrogenase oxidative metabolic activity in skeletal muscles of C57Bl\/6J mice. Next, hindlimb ischemia was induced via unilateral femoral vessel ligation in mice, followed by intramuscular AAV9\u2010Esrrg (or AAV9\u2010green fluorescent protein) gene delivery 24\u2009hours after injury. ERR\u03b3 overexpression increased ischemic neoangiogenesis and markers of endothelial activation, and significantly improved ischemic revascularization measured using laser Doppler flowmetry. Moreover, ERR\u03b3 overexpression restored succinate dehydrogenase oxidative metabolic capacity in ischemic muscle, which correlated with increased mitochondrial respiratory complex protein expression. Most importantly, myofiber size to number quantification revealed that AAV9\u2010Esrrg restores myofibrillar size and mitigates ischemia\u2010induced myopathy.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              These results demonstrate that intramuscular AAV9\u2010Esrrg delivery rescues ischemic pathology after hindlimb ischemia, underscoring that\n              <jats:italic>Esrrg<\/jats:italic>\n              gene therapy or pharmacological activation could be a promising strategy for the management of peripheral arterial disease\/critical limb ischemia.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.122.028880","type":"journal-article","created":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T09:38:56Z","timestamp":1691401136000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Estrogen\u2010Related Receptor Gamma Gene Therapy Promotes Therapeutic Angiogenesis and Muscle Recovery in Preclinical Model of PAD"],"prefix":"10.1161","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1174-416X","authenticated-orcid":false,"given":"Danesh H.","family":"Sopariwala","sequence":"first","affiliation":[{"name":"Brown Foundation Institute of Molecular Medicine McGovern Medical School at The University of Texas Health Science Center (UTHealth) Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0016-2718","authenticated-orcid":false,"given":"Andrea 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A.","family":"Narkar","sequence":"additional","affiliation":[{"name":"Brown Foundation Institute of Molecular Medicine McGovern Medical School at The University of Texas Health Science Center (UTHealth) Houston TX USA"},{"name":"Graduate School of Biomedical Sciences at UTHealth Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-021-00663-9"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.318243"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.318266"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.3390\/antiox9121304"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8122125"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.318242"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16593"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI67652"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.125401"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.01.019"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.266478"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00878-06"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12-212290"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-228296"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz128"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2013.16"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.122.028880","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T12:29:29Z","timestamp":1715603369000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.122.028880"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,15]]},"references-count":16,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2023,8,15]]}},"alternative-id":["10.1161\/JAHA.122.028880"],"URL":"https:\/\/doi.org\/10.1161\/jaha.122.028880","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,15]]},"assertion":[{"value":"2022-11-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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