{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:45:32Z","timestamp":1785818732623,"version":"3.56.0"},"reference-count":35,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Boehringer Ingelheim International GmbH"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Myeloid-derived growth factor (MYDGF) is a monocyte- and macrophage-secreted protein with anti-apoptotic and pro-angiogenic properties that has demonstrated protective effects in models of myocardial ischemia, but its role in peripheral ischemic injury has not been evaluated. We investigated the effects of recombinant human MYDGF (hMYDGF) in a murine hindlimb ischemia model. Male C57BL\/6 mice underwent femoral artery ligation and were treated with continuous subcutaneous infusion of recombinant hMYDGF, vehicle control, or vascular endothelial growth factor (VEGF) as a positive control. Limb perfusion was assessed longitudinally using laser speckle contrast imaging, and functional recovery was evaluated using standardized limb function scoring. Recombinant hMYDGF significantly improved blood flow recovery in the ischemic limb compared with vehicle at all post-surgical time points, achieving levels of perfusion comparable to VEGF. Improved perfusion translated into accelerated early functional recovery, with a greater proportion of recombinant hMYDGF-treated mice retaining normal toe flexion. Immunohistochemical analyses revealed significantly increased CD34+ endothelial cell staining in both quadriceps and gastrocnemius muscles in recombinant hMYDGF-treated mice, consistent with enhanced angiogenesis, while alpha-smooth muscle actin staining did not differ between groups. Collectively, these findings demonstrate that recombinant hMYDGF restores blood flow and accelerates functional recovery following ischemic injury, supporting its therapeutic potential for ischemic diseases.<\/jats:p>","DOI":"10.3390\/ijms27156903","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:57:56Z","timestamp":1785761876000},"page":"6903","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Human Myeloid-Derived Growth Factor Induces a Pro-Angiogenic Response and Functional Recovery in a Mouse Model of Peripheral Artery Disease"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9045-4740","authenticated-orcid":false,"given":"Anton","family":"Pekcec","sequence":"first","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Str. 65, 88400 Biberach an der Riss, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2295-437X","authenticated-orcid":false,"given":"Maria","family":"Myzithras","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, Ridgefield, CT 06877, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelia","family":"Walther","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim RCV GmbH & Co KG, Dr.-Boehringer-Gasse 5\u201311, 1120 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Ciossek","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Str. 65, 88400 Biberach an der Riss, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/nm.3778","article-title":"Myeloid-derived growth factor (C19orf10) mediates cardiac repair following myocardial infarction","volume":"21","author":"Reboll","year":"2015","journal-title":"Nat. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s10020-024-00874-z","article-title":"Myeloid-derived growth factor in diseases: Structure, function and mechanisms","volume":"30","author":"Chen","year":"2024","journal-title":"Mol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/s41401-023-01155-x","article-title":"Myeloid-derived growth factor suppresses VSMC dedifferentiation and attenuates postinjury neointimal formation in rats by activating S1PR2 and its downstream signaling","volume":"45","author":"Yang","year":"2024","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1093\/cvr\/cvag100","article-title":"Proteins targeting ischaemic-reperfusion injury and repair after myocardial infarction: A systematic literature review","volume":"122","author":"Gardev","year":"2026","journal-title":"Cardiovasc. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1007\/s12265-025-10641-y","article-title":"Mydgf enhances cardiac angiogenesis by upregulating FGF1","volume":"18","author":"Wang","year":"2025","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4136","DOI":"10.1111\/bph.15851","article-title":"Mucin-fused myeloid-derived growth factor (MYDGF164) exhibits a prolonged serum half-life and alleviates fibrosis in chronic kidney disease","volume":"179","author":"Du","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1111\/jcmm.14602","article-title":"Production of bioactive recombinant human myeloid-derived growth factor in Escherichia coli and its mechanism on vascular endothelial cell proliferation","volume":"24","author":"Zhao","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9100","DOI":"10.7150\/thno.44281","article-title":"Mydgf promotes Cardiomyocyte proliferation and Neonatal Heart regeneration","volume":"10","author":"Wang","year":"2020","journal-title":"Theranostics"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ultrasmedbio.2024.08.013","article-title":"Contrast-enhanced ultrasound of mouse models of hindlimb ischemia reveals persistent perfusion deficits and distinctive muscle perfusion patterns","volume":"51","author":"Becker","year":"2025","journal-title":"Ultrasound Med. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1080\/17576180.2026.2682870","article-title":"Preclinical pharmacokinetics of novel MYDGF for human PK and dose prediction","volume":"18","author":"Myzithras","year":"2026","journal-title":"Bioanalysis"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1007\/s11095-017-2219-y","article-title":"Influence of Molecular size on the clearance of antibody fragments","volume":"34","author":"Li","year":"2017","journal-title":"Pharm. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1007\/s11626-022-00709-3","article-title":"Role of Mydgf in the regulation of hypoxia\/reoxygenation-induced apoptosis in cardiac microvascular endothelial cells","volume":"58","author":"Wang","year":"2022","journal-title":"Vitr. Cell Dev. Biol. Anim."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"38429","DOI":"10.1021\/acsami.9b12043","article-title":"Injectable citrate-based hydrogel as an angiogenic biomaterial improves cardiac repair after myocardial infarction","volume":"11","author":"Yuan","year":"2019","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/S0008-6363(01)00546-6","article-title":"AAV-mediated VEGF gene transfer into skeletal muscle stimulates angiogenesis and improves blood flow in a rat hindlimb ischemia model","volume":"53","author":"Shimpo","year":"2002","journal-title":"Cardiovasc. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.jvs.2012.11.096","article-title":"The therapeutic effect of vascular endothelial growth factor gene- or heme oxygenase-1 gene-modified endothelial progenitor cells on neovascularization of rat hindlimb ischemia model","volume":"58","author":"Long","year":"2013","journal-title":"J. Vasc. Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/sj.gt.3301379","article-title":"Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models: Preclinical study for treatment of peripheral arterial disease","volume":"8","author":"Taniyama","year":"2001","journal-title":"Gene Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1161\/01.HYP.33.6.1379","article-title":"Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as cytokine supplement therapy","volume":"33","author":"Morishita","year":"1999","journal-title":"Hypertension"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.jconrel.2021.09.013","article-title":"Release of basic fibroblast growth factor from acoustically-responsive scaffolds promotes therapeutic angiogenesis in the hind limb ischemia model","volume":"338","author":"Jin","year":"2021","journal-title":"J. Control. Release"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/j.jvs.2011.02.060","article-title":"Efficacy of fragmin\/protamine microparticles containing fibroblast growth factor-2 (F\/P MPs\/FGF-2) to induce collateral vessels in a rabbit model of hindlimb ischemia","volume":"54","author":"Horio","year":"2011","journal-title":"J. Vasc. Surg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.trsl.2009.02.002","article-title":"Dual gene transfer of fibroblast growth factor-2 and platelet derived growth factor-BB using plasmid deoxyribonucleic acid promotes effective angiogenesis and arteriogenesis in a rodent model of hindlimb ischemia","volume":"153","author":"Arruda","year":"2009","journal-title":"Transl. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1016\/j.jvs.2015.06.140","article-title":"Biochemically engineered stromal cell-derived factor 1-alpha analog increases perfusion in the ischemic hind limb","volume":"64","author":"Edwards","year":"2016","journal-title":"J. Vasc. Surg."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1161\/CIRCULATIONAHA.110.991786","article-title":"Protease-resistant stromal cell-derived factor-1 for the treatment of experimental peripheral artery disease","volume":"123","author":"Segers","year":"2011","journal-title":"Circulation"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1038\/s12276-023-01096-9","article-title":"Vascular regeneration and skeletal muscle repair induced by long-term exposure to SDF-1\u03b1 derived from engineered mesenchymal stem cells after hindlimb ischemia","volume":"55","author":"Kim","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1038\/mt.2009.70","article-title":"VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: Results of the NORTHERN trial","volume":"17","author":"Stewart","year":"2009","journal-title":"Mol. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/s41434-022-00322-9","article-title":"AAV2-VEGF-B gene therapy failed to induce angiogenesis in ischemic porcine myocardium due to inflammatory responses","volume":"29","author":"Korpela","year":"2022","journal-title":"Gene Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.jss.2005.06.013","article-title":"Differential necrosis despite similar perfusion in mouse strains after ischemia","volume":"129","author":"Shireman","year":"2005","journal-title":"J. Surg. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"K\u00fcbler, M., G\u00f6tz, P., Braumandl, A., Beck, S., Ishikawa-Ankerhold, H., and Deindl, E. (2021). Impact of C57BL\/6J and SV-129 mouse strain differences on ischemia-induced postnatal angiogenesis and the associated leukocyte infiltration in a murine hindlimb model of ischemia. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111795"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"102232","DOI":"10.1016\/j.xpro.2023.102232","article-title":"Evaluation of post-natal angiogenesis in a mouse hind limb ischemia model","volume":"4","author":"Albiero","year":"2023","journal-title":"STAR. Protoc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3449","DOI":"10.1038\/s41598-020-60352-4","article-title":"Development of a two-stage limb ischemia model to better simulate human peripheral artery disease","volume":"10","author":"Krishna","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"H1124","DOI":"10.1152\/ajpheart.00470.2020","article-title":"A novel model of chronic limb ischemia to therapeutically evaluate the angiogenic effects of drug candidates","volume":"320","author":"Shimatani","year":"2021","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1177\/0271678X20943823","article-title":"The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research","volume":"40","author":"Hurst","year":"2020","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.jvs.2015.04.387","article-title":"Angiogenic properties of human placenta-derived adherent cells and efficacy in hindlimb ischemia","volume":"64","author":"Francki","year":"2016","journal-title":"J. Vasc. Surg."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1161\/01.CIR.0000079225.50817.71","article-title":"Impaired arteriogenic response to acute hindlimb ischemia in CD4-knockout mice","volume":"108","author":"Stabile","year":"2003","journal-title":"Circulation"},{"key":"ref_34","first-page":"128","article-title":"Search for appropriate experimental methods to create stable hind-limb ischemia in mouse","volume":"31","author":"Goto","year":"2006","journal-title":"Tokai J. Exp. Clin. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5093","DOI":"10.3892\/mmr.2015.4089","article-title":"Genetically modified human placenta-derived mesenchymal stem cells with FGF-2 and PDGF-BB enhance neovascularization in a model of hindlimb ischemia","volume":"12","author":"Yin","year":"2015","journal-title":"Mol. Med. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6903\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:14:15Z","timestamp":1785816855000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6903"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,1]]},"references-count":35,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156903"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156903","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,1]]}}}