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Transient receptor potential channel V4 (TRPV4), a key member of Ca<jats:sup>2+<\/jats:sup>\u2010permeable channels, plays a crucial role in maintaining vascular functions. However, the role and mechanisms of TRPV4 in aging\u2010related endothelial dysfunction remain incompletely understood. Here, we demonstrated a marked reduction in endothelial TRPV4 function without alterations in its expression, leading to abnormal endothelial Ca<jats:sup>2+<\/jats:sup> signaling and impaired vasodilation in aging mesenteric arteries. Employing transcriptome sequencing, co\u2010IP, and PLA assays, we characterized G protein\u2010coupled receptor 35 (GPR35) interacting with TRPV4, and abnormally enhanced interactions were found in aging endothelial cells. Subsequently, we revealed that intensive GPR35\u2010TRPV4 interaction significantly contributes to endothelial dysfunction during aging, utilizing TRPV4 endothelial\u2010specific knockout (TRPV4<jats:sub>EC<\/jats:sub><jats:sup>\u2212\/\u2212<\/jats:sup>), AAV\u2010FLT1\u2010shRNA (GPR35) mice, and GPR35 overexpressed\/knocked\u2010down HUVECs. Furthermore, molecular docking analysis and subsequent co\u2010IP and pressure myograph experiments indicated that both Thonningianin A and Carfilzomib efficiently restored the GPR35\u2010TRPV4 interaction, preventing endothelial dysfunction and vasodilation impairment. Our study identifies the crucial role of GPR35\u2010TRPV4 interaction in aging\u2010associated abnormal endothelial function and vascular tone modulation. Restoring GPR35\u2010TRPV4 interaction via Thonningianin A or Carfilzomib represents a promising precision approach for aging\u2010related endothelial dysfunction.<\/jats:p>","DOI":"10.1111\/acel.14469","type":"journal-article","created":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T05:39:20Z","timestamp":1735796360000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Investigating the Role of TRPV4 and GPR35 Interaction in Endothelial Dysfunction in Aging Mice"],"prefix":"10.1111","volume":"24","author":[{"given":"Xiaoxue","family":"Tian","sequence":"first","affiliation":[{"name":"Wuxi School of Medicine Jiangnan University  Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Kan","sequence":"additional","affiliation":[{"name":"Wuxi School of Medicine Jiangnan University  Wuxi 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