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Bioeng. Biotechnol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Previous studies have indicated that vascular endothelial growth factor B186 (VEGF-B186) supports coronary vascular growth in normal and ischemic myocardium. However, previous studies also indicated that induction of ventricular arrhythmias is a severe side effect preventing the use of VEGF-B186 in cardiac gene therapy, possibly mediated by binding to neuropilin 1 (NRP1). We have designed a novel VEGF-B186 variant, VEGF-B186R127S, which is resistant to proteolytic processing and unable to bind to NRP1. Here, we studied its effects on mouse heart to explore the mechanism of VEGF-B186-induced vascular growth along with its effects on cardiac performance.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Following the characterization of VEGF-B186R127S, we performed ultrasound-guided adenoviral VEGF-B186R127S gene transfers into the murine heart. Vascular growth and heart functions were analyzed using immunohistochemistry, RT-PCR, electrocardiogram and ultrasound examinations. Endothelial progenitor cells (EPCs) were isolated from the circulating blood and characterized. Also, <jats:italic>in vitro<\/jats:italic> experiments were carried out in cardiac endothelial cells with adenoviral vectors.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> The proteolytically resistant VEGF-B186R127S significantly induced vascular growth in mouse heart. Interestingly, VEGF-B186R127S gene transfer increased the number of circulating EPCs that secreted VEGF-A. Other proangiogenic factors were also present in plasma and heart tissue after the VEGF-B186R127S gene transfer. Importantly, VEGF-B186R127S gene transfer did not cause any side effects, such as arrhythmias.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> VEGF-B186R127S induces vascular growth in mouse heart by recruiting EPCs. VEGF-B186R127S is a novel therapeutic agent for cardiac therapeutic angiogenesis to rescue myocardial tissue after an ischemic insult.<\/jats:p>","DOI":"10.3389\/fbioe.2022.907538","type":"journal-article","created":{"date-parts":[[2022,8,4]],"date-time":"2022-08-04T04:31:53Z","timestamp":1659587513000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Novel Designed Proteolytically Resistant VEGF-B186R127S Promotes Angiogenesis in Mouse Heart by Recruiting Endothelial Progenitor Cells"],"prefix":"10.3389","volume":"10","author":[{"given":"Rahul","family":"Mallick","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Gurzeler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pyry I.","family":"Toivanen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiina","family":"Nieminen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seppo","family":"Yl\u00e4-Herttuala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"471","DOI":"10.3390\/cells8050471","article-title":"Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology","volume":"8","author":"Akwii","year":"2019","journal-title":"Cells"},{"key":"B2","doi-asserted-by":"publisher","first-page":"H1090","DOI":"10.1152\/ajpheart.00473.2010","article-title":"Why Is the Subendocardium More Vulnerable to Ischemia? 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