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Using fructose-fed rats (FFRs), a rat model of MetS, we investigated the effects of tadalafil (a phosphodiesterase-5 inhibitor) on MetS-associated chronic bladder ischemia and bladder overactivity. Phenotypes of the OAB, including increased micturition frequency and a shortened intercontractile interval in cystometry, were observed in FFRs, together with reduced bladder blood perfusion (in empty bladders) via laser color Doppler imaging and elevated serum nitrite levels, suggesting chronic ischemia-related bladder dysfunction. Treatment with tadalafil (2 mg\/kg) promoted pelvic angiogenesis, as shown by magnetic resonance imaging, and increased VEGF and p-eNOS overexpression in the bladder. This treatment restored bladder perfusion and alleviated bladder overactivity without significantly altering most MetS parameters. At the molecular level, FFRs exhibited increased ischemia markers (NGF, HIF-2\u03b1, and AMPK-\u03b12) and decreased p-AMPK-\u03b12, along with elevated proinflammatory mediators (ICAM-1, nuclear NF-\u03baB, COX-2, IL-1\u03b2, IL-6, and TNF-\u03b1), enhanced mitochondria biogenesis (PGC-1\u03b1, TFAM, and mitochondria DNA copy number), oxidative stress (decreased nuclear NRF2, increase MnSOD and 8-OHdG staining), and tissue fibrosis (increased TGF-\u03b21, collagen I, and fibronectin). Tadalafil treatment improved these effects. Together, these findings suggest that tadalafil may promote VEGF-associated angiogenesis, enhance p-eNOS staining in the bladder vasculature, normalize bladder perfusion in microcirculation, and reduce serum nitrite levels. Consequently, tadalafil mitigates the adverse effects of chronic ischemia\/hypoxia, improving bladder overactivity. We elucidated the mechanisms underlying the tadalafil-mediated amelioration of MetS-associated OAB symptoms.<\/jats:p>","DOI":"10.3390\/ijms26031363","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T04:47:31Z","timestamp":1738817251000},"page":"1363","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Tadalafil Ameliorates Chronic Ischemia-Associated Bladder Overactivity in Fructose-Fed Rats by Exerting Pelvic Angiogenesis and Enhancing p-eNOS Expression"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0701-2285","authenticated-orcid":false,"given":"Wei-Chia","family":"Lee","sequence":"first","affiliation":[{"name":"Division of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Lu","sequence":"additional","affiliation":[{"name":"Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan"},{"name":"Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7441-448X","authenticated-orcid":false,"given":"Chia-Hao","family":"Su","sequence":"additional","affiliation":[{"name":"Center for General Education, Chang Gung University, Taoyuan 333, Taiwan"},{"name":"Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan"},{"name":"Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7059-6407","authenticated-orcid":false,"given":"You-Lin","family":"Tain","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7297-6788","authenticated-orcid":false,"given":"Kay L. H.","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7470-528X","authenticated-orcid":false,"given":"Chien-Ning","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan"},{"name":"School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2821-2235","authenticated-orcid":false,"given":"Hong-Tai","family":"Tzeng","sequence":"additional","affiliation":[{"name":"Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/luts.12193","article-title":"Prevalence of overactive bladder in China, Taiwan and South Korea: Results from a cross-sectional, population-based study","volume":"11","author":"Chuang","year":"2019","journal-title":"Low. 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