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Ca<jats:sup>2+<\/jats:sup>\u2010activated K<jats:sup>+<\/jats:sup> (K<jats:sub>Ca<\/jats:sub>) channels are known to be associated with transient receptor potential (TRP) channels, which are important for regulating endothelial function. But how TRPV4 channels interacts with K<jats:sub>Ca<\/jats:sub> channels in regulating coronary vascular tone in HFD mice requires further exploration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>TRPV4 channel activity was assessed by fluorescent Ca<jats:sup>2+<\/jats:sup> imaging. Interactions between TRPV4 and K<jats:sub>Ca<\/jats:sub>3.1 channels were verified by co\u2010immunoprecipitation and immunofluorescence resonance energy transfer (FRET), and their binding site was found by site\u2010directed mutagenesis. Endothelium\u2010specific TRPV4 knockout (TRPV4<jats:sub>EC<\/jats:sub><jats:sup>\u2212\/\u2212<\/jats:sup>) mice were used to study the effect of the interactions between TRPV4\u2010K<jats:sub>Ca<\/jats:sub>3.1 channels on coronary vascular tone. Coronary blood flow was measured by Doppler ultrasound device.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>TRPV4 channels were involved in regulating coronary vascular tone, through coupling with a Ca<jats:sup>2+<\/jats:sup>\u2010sensitive K<jats:sup>+<\/jats:sup> channel (K<jats:sub>Ca<\/jats:sub>3.1) in CAECs, affecting vasodilation and coronary blood flow. In mice fed a HFD diet, the coupling was damaged by a high concentration of plasma 1\u2010heptadecanoyl\u20102\u2010hydroxy\u2010sn\u2010glycero\u20103\u2010phosphocholine. Using a bridging approach, we then identified folic acid as an effective drug to repair the uncoupled TRPV4\u2010K<jats:sub>Ca<\/jats:sub>3.1 channels and to improve coronary arterial function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Our data highlight the importance of coupling between TRPV4 and K<jats:sub>Ca<\/jats:sub>3.1 channels in the regulation of coronary vascular tone and provide a novel strategy for developing new drugs to reduce the incidence of cardiovascular events.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16082","type":"journal-article","created":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T05:25:28Z","timestamp":1680499528000},"page":"2266-2279","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Functional role of coupling the endothelial TRPV4 and K<sub>Ca<\/sub>3.1 channels in regulating coronary vascular 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