{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:53:57Z","timestamp":1790096037013,"version":"4.0.1"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T00:00:00Z","timestamp":1616112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Angiogenesis is an important process under both physiological and pathophysiological conditions. Here we investigated the role and the underlying mechanism of PD-1 in hindlimb ischemia-induced inflammation and angiogenesis in mice. We found that inhibition of PD-1 by genetic PD-1 knockout or pharmacological PD-1 blocking antibodies dramatically attenuated hindlimb blood perfusion, angiogenesis, and exercise capacity in mice after femoral artery ligation. Mechanistically, we found that PD-1 knockout significantly exacerbated ischemia-induced muscle oxidative stress, leukocyte infiltration and IFN-\u03b3 production before abnormal angiogenesis in these mice. In addition, we found that the percentages of IFN-\u03b3 positive macrophages and CD8 T cells were significantly increased in P-1 knockout mice after hindlimb ischemia. Macrophages were the major leukocyte subset infiltrated in skeletal muscle, which were responsible for the enhanced muscle leukocyte-derived IFN-\u03b3 production in PD-1 knockout mice after hindlimb ischemia. Moreover, we demonstrated that IFN-\u03b3 significantly attenuated vascular endothelial cell proliferation, tube formation and migration <jats:italic>in vitro<\/jats:italic>. IFN-\u03b3 also significantly enhanced vascular endothelial cell apoptosis. In addition, the total number of TNF-\u03b1 positive leukocytes\/muscle weight were significantly increased in PD-1<jats:sup>-\/-<\/jats:sup> mice after hindlimb ischemia. These data indicate that PD-1 exerts an important role in ischemia-induced muscle inflammation and angiogenesis.<\/jats:p>","DOI":"10.3389\/fimmu.2021.586429","type":"journal-article","created":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T04:32:58Z","timestamp":1616128378000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Pharmacological and Genetic Inhibition of PD-1 Demonstrate an Important Role of PD-1 in Ischemia-Induced Skeletal Muscle Inflammation, Oxidative Stress, and Angiogenesis"],"prefix":"10.3389","volume":"12","author":[{"given":"Xiaoguang","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihua","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peijie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000232542.42968.e3","article-title":"Transcriptional regulators of angiogenesis","volume":"26","author":"Hamik","year":"2006","journal-title":"Arterioscl Throm Vas"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-017-9562-9","article-title":"Tumor angiogenesis and vascular normalization: alternative therapeutic targets","volume":"20","author":"Viallard","year":"2017","journal-title":"Angiogenesis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2337\/db19-0713","article-title":"PI3Kdelta as a Novel Therapeutic Target in Pathological Angiogenesis","volume":"69","author":"Wu","year":"2020","journal-title":"Diabetes"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-015-9475-4","article-title":"KSHV induces aerobic glycolysis and angiogenesis through HIF-1-dependent upregulation of pyruvate kinase 2 in Kaposi\u2019s sarcoma","volume":"18","author":"Ma","year":"2015","journal-title":"Angiogenesis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.025490","article-title":"Annex BH. 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