Functional role of coupling the endothelial TRPV4 and KCa3.1 channels in regulating coronary vascular tone

Background and PurposeHigh-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+ (K-Ca) 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-Ca channels in regulating coronary vascular tone in HFD mice requires further exploration. Experimental ApproachTRPV4 channel activity was assessed by fluorescent Ca2+ imaging. Interactions between TRPV4 and K(Ca)3.1 channels were verified by co-immunoprecipitation and immunofluorescence resonance energy transfer (FRET), and their binding site was found by site-directed mutagenesis. Endothelium-specific TRPV4 knockout (TRPV4(EC)(-/-)) mice were used to study the effect of the interactions between TRPV4-K(Ca)3.1 channels on coronary vascular tone. Coronary blood flow was measured by Doppler ultrasound device. Key ResultsTRPV4 channels were involved in regulating coronary vascular tone, through coupling with a Ca2+-sensitive K+ channel (K(Ca)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-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-K(Ca)3.1 channels and to improve coronary arterial function. Conclusion and ImplicationsOur data highlight the importance of coupling between TRPV4 and K(Ca)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.

Automated summary

A high-fat diet leads to dysregulated pathways in coronary artery endothelial cells and increases the risk of coronary artery diseases. The coupling between TRPV4 and K(Ca)3.1 channels plays an important role in regulating coronary vascular tone. Folic acid can repair the uncoupled channels and improve coronary arterial function.