{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T22:04:33Z","timestamp":1792447473782,"version":"4.5.0"},"reference-count":30,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T00:00:00Z","timestamp":1690848000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Lymphatic Research and Biology"],"published-print":{"date-parts":[[2023,8,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">:<\/jats:italic>\n                      Lymphedema is an intractable disease with no curative treatment available. Conservative treatment is the mainstay, and new drug treatment options are strongly needed. The purpose of this study was to investigate the effect of roxadustat, a prolyl-4-hydroxylase inhibitor, on lymphangiogenesis and its therapeutic effect on lymphedema in a radiation-free mouse hindlimb lymphedema model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">:<\/jats:italic>\n                      Male C57BL\/6N mice (8\u201310 weeks old) were used for the lymphedema model. Mice were randomized to an experimental group receiving roxadustat or a control group. The circumferential ratio of the hindlimbs was evaluated, and lymphatic flow of the hindlimbs was compared by fluorescent lymphography up to 28 days postoperatively. The roxadustat group showed an early improvement in hindlimb circumference and stasis of lymphatic flow. The number and area of lymphatic vessels on postoperative day 7 were significantly larger and smaller, respectively, in the roxadustat group compared with the control group. Skin thickness and macrophage infiltration on postoperative day 7 were significantly reduced in the roxadustat group compared with the control group. The relative mRNA expression of hypoxia-inducible factor-1\u03b1 (\n                      <jats:italic toggle=\"yes\">Hif-1\u03b1<\/jats:italic>\n                      ), vascular endothelial growth factor receptor-3 (\n                      <jats:italic toggle=\"yes\">VEGFR-3<\/jats:italic>\n                      ), vascular endothelial growth factor-C (\n                      <jats:italic toggle=\"yes\">VEGF-C<\/jats:italic>\n                      ), and Prospero homeobox 1 (\n                      <jats:italic toggle=\"yes\">Prox1<\/jats:italic>\n                      ) on postoperative day 4 was significantly higher in the roxadustat group compared with the control group.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">:<\/jats:italic>\n                      Roxadustat demonstrated a therapeutic effect in a murine model of hindlimb lymphedema through promotion of lymphangiogenesis through the activation of HIF-1\u03b1, VEGF-C, VEGFR-3, and Prox1, suggesting the potential of roxadustat as a therapeutic option in lymphedema.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/lrb.2022.0071","type":"journal-article","created":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T09:52:50Z","timestamp":1678182770000},"page":"372-380","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":5,"title":["Therapeutic Potential of the Prolyl Hydroxylase Inhibitor Roxadustat in a Mouse Hindlimb Lymphedema Model"],"prefix":"10.1177","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7952-010X","authenticated-orcid":false,"given":"Yoshitada","family":"Hoshino","sequence":"first","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Osawa","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emi","family":"Funayama","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6068-7276","authenticated-orcid":false,"given":"Kosuke","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4180-6556","authenticated-orcid":false,"given":"Takahiro","family":"Miura","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Hojo","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhei","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3612-8201","authenticated-orcid":false,"given":"Taku","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2023,8,22]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04480"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2017.03.022"},{"key":"e_1_3_5_4_2","first-page":"10","article-title":"A meta-analysis of 37 studies on the effectiveness of microsurgical techniques for lymphedema","author":"Kong X","year":"2022","unstructured":"Kong X, , Du J, , Du X, et al. 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HIF-1alpha contributes to tube malformation of human lymphatic endothelial cells by upregulating VEGFR-3. 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