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The present study investigated a potential role for chrysin, a naturally occurring flavonoid, in promoting angiogenesis in hindlimb ischemia (HLI) rat model. Rats were allocated into four groups: (1) sham\u2010operated control, (2) HLI: subjected to unilateral femoral artery ligation, (3) HLI\u2009+\u2009chrysin: received 100\u2009mg\/kg, i.p. chrysin immediately after HLI, and (4) HLI\u2009+\u2009chrysin\u2009+\u2009rapamycin: received 6\u2009mg\/kg\/day rapamycin i.p. for 5 days then subjected to HLI and dosed with 100\u2009mg\/kg chrysin, i.p. Rats were killed 18\u2009h later and gastrocnemius muscles were collected and divided into parts for (1) immunohistochemistry detection of CD31 and CD105, (2) qRT\u2010PCR analysis of eNOS and VEGFR2, (3) colorimetric analysis of NO, (4) ELISA estimation of TGF\u2010\u03b2, VEGF, ATG5 and Beclin\u20101, and (5) Western blot analysis of p\u2010PI3K, PI3K, p\u2010Akt, Akt, p\u2010mTOR, mTOR, and HIF\u20101\u03b1. Chrysin significantly enhanced microvessels growth in HLI muscles as indicated by increased CD31 and CD105 levels and decreased TGF\u2010\u03b2. Chrysin's proangiogenic effect is potentially mediated by increased VEGF,\u00a0VEGFR2 and activation of PI3K\/AKT\/mTOR pathway, which promoted eNOS and NO levels as it was reversed by the mTOR inhibitor, rapamycin. Chrysin also inhibited autophagy as it decreased ATG5 and Beclin\u20101. The current study shows that chrysin possesses a proangiogenic effect in HLI rats and might be useful in patients with PAD.<\/jats:p>","DOI":"10.1002\/ddr.21954","type":"journal-article","created":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T01:34:55Z","timestamp":1654479295000},"page":"1226-1237","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Chrysin promotes angiogenesis in rat hindlimb ischemia: Impact on PI3K\/Akt\/mTOR signaling pathway and autophagy"],"prefix":"10.1002","volume":"83","author":[{"given":"Rehab","family":"Kamel","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Helwan University  Cairo Egypt"},{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Ahram Canadian University  Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Engy M.","family":"El Morsy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Helwan University  Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7519-7587","authenticated-orcid":false,"given":"Marwa E.","family":"Elsherbiny","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Ahram Canadian University  Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Nour\u2010Eldin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy University of Sadat City (USC)  Menoufia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,6,5]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00381.2001"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.01.021"},{"issue":"4","key":"e_1_2_10_4_1","first-page":"645","article-title":"Peripheral arterial disease in the elderly","volume":"2","author":"Aronow W. 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