{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:40:40Z","timestamp":1784547640278,"version":"3.55.0"},"reference-count":27,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T00:00:00Z","timestamp":1730678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"CIHR","doi-asserted-by":"publisher","award":["PJT-152990"],"award-info":[{"award-number":["PJT-152990"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"CIHR","doi-asserted-by":"publisher","award":["R4829A15"],"award-info":[{"award-number":["R4829A15"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"CIHR","doi-asserted-by":"publisher","award":["IRF-18-21"],"award-info":[{"award-number":["IRF-18-21"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"NSERC","doi-asserted-by":"publisher","award":["PJT-152990"],"award-info":[{"award-number":["PJT-152990"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"NSERC","doi-asserted-by":"publisher","award":["R4829A15"],"award-info":[{"award-number":["R4829A15"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"NSERC","doi-asserted-by":"publisher","award":["IRF-18-21"],"award-info":[{"award-number":["IRF-18-21"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Lawson Internal Research Fund Studentship Award 2021","award":["PJT-152990"],"award-info":[{"award-number":["PJT-152990"]}]},{"name":"Lawson Internal Research Fund Studentship Award 2021","award":["R4829A15"],"award-info":[{"award-number":["R4829A15"]}]},{"name":"Lawson Internal Research Fund Studentship Award 2021","award":["IRF-18-21"],"award-info":[{"award-number":["IRF-18-21"]}]},{"name":"CHRI Trainee Scholarship 2020","award":["PJT-152990"],"award-info":[{"award-number":["PJT-152990"]}]},{"name":"CHRI Trainee Scholarship 2020","award":["R4829A15"],"award-info":[{"award-number":["R4829A15"]}]},{"name":"CHRI Trainee Scholarship 2020","award":["IRF-18-21"],"award-info":[{"award-number":["IRF-18-21"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Duchenne muscular dystrophy (DMD) is a degenerative neuromuscular disease caused by a lack of functional dystrophin. Ang 1 paracrine signalling maintains the endothelial barrier of blood vessels, preventing plasma leakage. Chronic inflammation, a consequence of DMD, causes endothelial barrier dysfunction in skeletal muscle. We aim to elucidate changes in the DMD mouse\u2019s gastrocnemius microvascular niche following local administration of Ang 1. Gastrocnemii were collected from eight-week-old mdx\/utrn+\/\u2212 and healthy mice. Additional DMD cohort received an intramuscular injection of Ang 1 to gastrocnemius and contralateral control. Gastrocnemii were collected for analysis after two weeks. Using immunohistochemistry and real-time quantitative reverse transcription, we demonstrated an abundance of endothelial cells in DMD mouse\u2019s gastrocnemius, but morphology and gene expression were altered. Myofiber perimeters were shorter in DMD mice. Following Ang 1 treatment, fewer endothelial cells were present, and microvessels were more circular. Vegfr1, Vegfr2, and Vegfa expression in Ang 1-treated gastronemii increased, while myofiber size distribution was consistent with vehicle-only gastrocnemii. These results suggest robust angiogenesis in DMD mice, but essential genes were underexpressed\u2014furthermore, exogenous Ang 1 attenuated angiogenesis. Consequentially, gene expression increased. The impact must be investigated further, as Ang 1 therapy may be pivotal in restoring the skeletal muscle microvascular niche.<\/jats:p>","DOI":"10.3390\/ijms252111824","type":"journal-article","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T03:57:34Z","timestamp":1730692654000},"page":"11824","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Angiopoietin 1 Attenuates Dysregulated Angiogenesis in the Gastrocnemius of DMD Mice"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0084-3553","authenticated-orcid":false,"given":"Andrew","family":"McClennan","sequence":"first","affiliation":[{"name":"Department of Medical Biophysics, Western University, London, ON N6A 5C1, Canada"},{"name":"Imaging Program, The Lawson Health Research Institute, London, ON N6C 2R5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4409-5120","authenticated-orcid":false,"given":"Lisa","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Department of Medical Biophysics, Western University, London, ON N6A 5C1, Canada"},{"name":"Imaging Program, The Lawson Health Research Institute, London, ON N6C 2R5, Canada"},{"name":"Department of Anatomy and Cell Biology, Western University, London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1038\/nm.1852","article-title":"PlGF-MMP-9-expressing cells restore microcirculation and efficacy of cell therapy in aged dystrophic muscle","volume":"14","author":"Gargioli","year":"2008","journal-title":"Nat. Med."},{"key":"ref_2","first-page":"467","article-title":"Anomalies of regulation of the muscular microcirculation in children having progressive muscular dystrophy compared to normal children of the same age","volume":"13","author":"Demos","year":"1968","journal-title":"Rev. Fr. Etud. Clin. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1161\/01.ATV.0000118683.99628.42","article-title":"Absence of Dystrophin in Mice Reduces NO-Dependent Vascular Function and Vascular Density: Total Recovery after a Treatment with the Aminoglycoside Gentamicin","volume":"24","author":"Loufrani","year":"2004","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1161\/ATVBAHA.112.301172","article-title":"Angiogenic impairment of the vascular endothelium: A novel mechanism and potential therapeutic target in muscular dystrophy","volume":"33","author":"Palladino","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1016\/j.ajpath.2015.05.009","article-title":"Structural and Functional Alterations of Skeletal Muscle Microvasculature in Dystrophin-Deficient mdx Mice","volume":"185","author":"Latroche","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1038\/mt.2009.136","article-title":"Effect of VEGF on the regenerative capacity of muscle stem cells in dystrophic skeletal muscle","volume":"17","author":"Deasy","year":"2009","journal-title":"Mol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3737","DOI":"10.1096\/fj.07-8459com","article-title":"VEGF overexpression via adeno-associated virus gene transfer promotes skeletal muscle regeneration and enhances muscle function in mdx mice","volume":"21","author":"Messina","year":"2007","journal-title":"FASEB J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1093\/hmg\/ddab120","article-title":"Combined gene therapy via VEGF and mini-dystrophin synergistically improves pathologies in temporalis muscle of dystrophin\/utrophin double knockout mice","volume":"30","author":"Xin","year":"2021","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2511","DOI":"10.1126\/science.286.5449.2511","article-title":"Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1","volume":"286","author":"Thurston","year":"1999","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gutpell, K.M., Tasevski, N., Wong, B., Hrinivich, W.T., Su, F., Hadway, J., Desjardins, L., Lee, T.Y., and Hoffman, L.M. (2017). ANG1 treatment reduces muscle pathology and prevents a decline in perfusion in DMD mice. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174315"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.canlet.2012.08.018","article-title":"Angiopoietins in angiogenesis","volume":"328","author":"Fagiani","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.devcel.2007.10.019","article-title":"Angiopoietin-1 Prevents VEGF-Induced Endothelial Permeability by Sequestering Src through mDia","volume":"14","author":"Gavard","year":"2008","journal-title":"Dev. Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e957508","DOI":"10.4161\/21688362.2014.957508","article-title":"The angiopoietin-Tie2 signaling axis in the vascular leakage of systemic inflammation","volume":"3","author":"Milam","year":"2015","journal-title":"Tissue Barriers"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1161\/01.RES.86.1.24","article-title":"Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3\u2032-kinase\/Akt signal transduction pathway","volume":"86","author":"Kim","year":"2000","journal-title":"Circ. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1159\/000324950","article-title":"Angiogenic factors","volume":"170","author":"Khoury","year":"2011","journal-title":"Contrib. Nephrol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.1084\/jem.20110525","article-title":"Dissociation of VE-PTP from ve-cadherin is required for leukocyte extravasation and for VEGF-induced vascular permeability in vivo","volume":"208","author":"Broermann","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1038\/ncb1486","article-title":"VEGF Controls endothelial-cell permeability promoting \u03b2-arrestin-dependent Endocytosis VE-cadherin","volume":"8","author":"Gavard","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lin, Y., McClennan, A., and Hoffman, L. (2023). Characterization of the Ang\/Tie2 Signaling Pathway in the Diaphragm Muscle of DMD Mice. Biomedicines, 11.","DOI":"10.3390\/biomedicines11082265"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ahmad, N., Welch, I., Grange, R., Hadway, J., Dhanvantari, S., Hill, D., Lee, T.Y., and Hoffman, L.M. (2011). Use of imaging biomarkers to assess perfusion and glucose metabolism in the skeletal muscle of dystrophic mice. BMC Musculoskelet. Disord., 12.","DOI":"10.1186\/1471-2474-12-127"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1161\/ATVBAHA.117.309993","article-title":"Tortuous Microvessels Contribute to Wound Healing via Sprouting Angiogenesis","volume":"37","author":"Chong","year":"2017","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/35025220","article-title":"Angiogenesis in cancer and other diseases, insight review articles","volume":"407","author":"Carmeliet","year":"2000","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/S0002-9440(10)65006-7","article-title":"Openings between defective endothelial cells explain tumor vessel leakiness","volume":"156","author":"Hashizume","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"C1367","DOI":"10.1152\/ajpcell.2001.280.6.C1367","article-title":"Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis","volume":"280","author":"Dor","year":"2001","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gutpell, K.M., Hrinivich, W.T., and Hoffman, L.M. (2015). Skeletal muscle fibrosis in the mdx\/utrn+\/-mouse validates its suitability as a murine model of duchenne muscular dystrophy. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117306"},{"key":"ref_25","first-page":"36","article-title":"Image processing with imageJ","volume":"11","author":"Ram","year":"2004","journal-title":"Biophotonics Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1139\/h97-002","article-title":"A new measurement of tissue capillarity: The capillary-to-fibre perimeter exchange index","volume":"22","author":"Hepple","year":"1997","journal-title":"Can. J. Appl. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Hildyard, J.C.W., Finch, A.M., and Wells, D.J. (2019). Identification of qPCR reference genes suitable for normalizing gene expression in the mdx mouse model of Duchenne muscular dystrophy. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0211384"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/21\/11824\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:27:58Z","timestamp":1760113678000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/21\/11824"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,4]]},"references-count":27,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["ijms252111824"],"URL":"https:\/\/doi.org\/10.3390\/ijms252111824","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,4]]}}}