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The transient receptor potential cation channel subfamily C member 5 (TRPC5) is known to regulate angiogenesis, but its role in the context of obesity\u2010related MI is unclear. Here, we show that TRPC5 expression is downregulated in obese mice hearts following MI, resulting in compromised angiogenic function. Riluzole, an FDA\u2010approved drug for amyotrophic lateral sclerosis, activates TRPC5 and restores the migration, sprouting, and tube formation function of coronary artery endothelial cells isolated from diet\u2010induced obese (DIO) MI mice. In obese mice, riluzole enhances post\u2010MI neovascularization, reduces infarct size, and improves cardiac function. Notably, TRPC5\u2010mediated angiogenesis requires aquaporin\u20101 (AQP1), whose expression is regulated by TRPC5 via the nuclear factor of activated T cells 3 (NFATc3) transcription factor. Silencing AQP1 abolishes the pro\u2010angiogenic effects of TRPC5 activation, establishing AQP1 as a critical downstream effector. In conclusion, our data provide evidence that the TRPC5\u2010NFATc3\u2010AQP1 pathway is essential for post\u2010MI angiogenesis in obesity and support riluzole as a promising therapeutic approach to enhance angiogenesis in obese individuals following MI.<\/jats:p>","DOI":"10.1002\/cph4.70048","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T05:06:49Z","timestamp":1758085609000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Obesity Impacts Post\u2010Myocardial Infarction Neovascularization by Downregulating\n                    <scp>AQP1<\/scp>\n                    Expression via the\n                    <scp>TRPC5<\/scp>\n                    \u2010\n                    <scp>NFATc3<\/scp>\n                    Signaling Pathway"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2373-9774","authenticated-orcid":false,"given":"Mengru","family":"Gao","sequence":"first","affiliation":[{"name":"Wuxi School of Medicine Jiangnan University  Wuxi China"},{"name":"School of Food Science and Technology Jiangnan University  Wuxi Jiangsu China"},{"name":"MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine Jiangnan University  Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Han","sequence":"additional","affiliation":[{"name":"Wuxi School of Medicine Jiangnan University  Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Wuxi School of Medicine Jiangnan University  Wuxi China"},{"name":"MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine Jiangnan University  Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wen","sequence":"additional","affiliation":[{"name":"Wuxi School of Medicine Jiangnan University  Wuxi China"},{"name":"MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine Jiangnan University  Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Feng","sequence":"additional","affiliation":[{"name":"Wuxi School of Medicine Jiangnan University  Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Zhou","sequence":"additional","affiliation":[{"name":"Wuxi School of Medicine Jiangnan University  Wuxi China"},{"name":"MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine Jiangnan University  Wuxi China"},{"name":"Food Nutrition and Human Health Interdisciplinary Center, Wuxi School of Medicine and School of Food Science and Technology, Wuxi School of Medicine Jiangnan University  Wuxi China"},{"name":"Affiliated Hospital of Jiangnan University  Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2014.01.020"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.036065"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-017-3126-7"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa070829"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.acthis.2014.02.010"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e07-08-0765"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)30054-X"},{"key":"e_1_2_8_9_1","first-page":"3","article-title":"Coronary Artery Disease: Medical Therapy Is Sometimes Best. 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