LAUSR

BACKGROUND AND PURPOSE High-fat diet (HFD) induces dysregulated pathways in coronary artery endothelial cells (CAECs), which leads to altered regulation of vascular tone, tissue perfusion and increases the risk of coronary artery diseases. Ca2+ -activated K+ channels (KCa) are known to be associated with transient receptor potential (TRP) channels, which is important for regulating endothelial function. But how TRPV4 interacts with KCa in regulating coronary vascular tone in HFD mice requires further exploration. EXPERIMENTAL APPROACH TRPV4 activity was assessed by fluorescent Ca2+ imaging. The TRPV4-KCa3.1 interaction was verified by co-immunoprecipitation and Immunofluorescence resonance energy transfer (FRET), and their binding site was found by site-directed mutagenesis. Endothelium-specific TRPV4 knockout (TRPV4EC -/- ) mice were used to study the effect of the TRPV4-KCa3.1 interaction on coronary vascular tone. Coronary blood flow was measured by Doppler ultrasound device. KEY RESULTS Here, we reported that TRPV4 was involved in the regulation of coronary vascular tone. Importantly, TRPV4 formed a coupling with Ca2+ -sensitive K+ channel KCa3.1 in CAECs, regulating vasodilation and coronary blood flow. In HFD mice, the coupling was damaged by a high concentration of plasma 1-heptadecanoyl-2-hydroxy-sn-glycero-3-phosphocholine. Using a bridging approach, we then identified folic acid as an effective drug to repair the uncoupled TRPV4-KCa3.1 and to improve coronary arterial function. CONCLUSION AND IMPLICATIONS Our data highlight the importance of TRPV4-KCa3.1 coupling in the regulation of coronary vascular tone and provide a novel strategy for developing new drugs to reduce the incidence of cardiovascular events.