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The angiopoietin-Tie2 signaling pathway plays a critical role in blood vessel development, formation, remodeling, and peripheral nerve regeneration. Therefore, strategies for activating the Tie2 signaling pathway have been developed as potential therapies for neurovascular diseases. Here, we developed a human Tie2-agonistic antibody (MT-100) that not only resists Ang-2 antagonism and activates Tie2 signaling but also regulates a novel target, sushi repeat-containing protein X-linked 2 (Srpx2). This regulation led to the survival of vascular and neuronal cells, a reduction in the production of reactive oxygen species (ROS), activation of the PI3K\/AKT\/eNOS signaling pathway, increased expression of neurotrophic factors, and ultimately alleviation of ED in diabetic mice. Our findings not only provide conclusive evidence that MT-100 is a promising therapeutic strategy for the treatment of diabetic ED but also suggest it has substantial clinical applications for other complications associated with diabetes.<\/jats:p>","DOI":"10.1038\/s12276-024-01373-1","type":"journal-article","created":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T01:02:31Z","timestamp":1735693351000},"page":"104-117","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["MT-100, a human Tie2-agonistic antibody, improves penile neurovasculature in diabetic mice via the novel target Srpx2"],"prefix":"10.1038","volume":"57","author":[{"given":"Fang-Yuan","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young-Lai","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fitri Rahma","family":"Fridayana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lashkari","family":"Niloofar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minh Nhat","family":"Vo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Limanjaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi-Hye","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyeon","family":"Ock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7214-7536","authenticated-orcid":false,"given":"Seon-Jin","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2512-7337","authenticated-orcid":false,"given":"Guo Nan","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nam-Kyung","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Kan","family":"Ryu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,1]]},"reference":[{"key":"1373_CR1","doi-asserted-by":"crossref","unstructured":"NIH consensus conference. 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Essential role of brain-derived neurotrophic factor (bdnf) in diabetic erectile dysfunction. Andrologia 50, e12924 (2018).","journal-title":"Andrologia"},{"key":"1373_CR5","doi-asserted-by":"crossref","first-page":"969","DOI":"10.2337\/db10-0354","volume":"60","author":"HR Jin","year":"2011","unstructured":"Jin, H. R. et al. Intracavernous delivery of a designed angiopoietin-1 variant rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse. Diabetes 60, 969\u2013980 (2011).","journal-title":"Diabetes"},{"key":"1373_CR6","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1016\/j.jsxm.2017.02.009","volume":"14","author":"YC Lee","year":"2017","unstructured":"Lee, Y. C. et al. Associations of VEGF gene polymorphisms with erectile dysfunction and related risk factors. 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