Functional role of coupling the endothelial TRPV4 and K_Ca3.1 channels in regulating coronary vascular tone

Abstract

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. Ca 2+ -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 Approach: TRPV4 channel activity was assessed by fluorescent Ca 2+ imaging. Interactions between TRPV4 and K Ca 3.1 channels were verified by coimmunoprecipitation and immunofluorescence resonance energy transfer (FRET), and their binding site was found by site-directed mutagenesis. Endothelium-specific TRPV4 knockout (TRPV4 EC À/À ) 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 Results: TRPV4 channels were involved in regulating coronary vascular tone, through coupling with a Ca 2+ -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 Implications:Our 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.

Establishing an ANO1-Based Cell Model for High-Throughput Screening Targeting TRPV4 Regulators

“…TRPV4 modulators can be used as therapeutic targets for a variety of diseases, such as TRPV4 activators that reduce atherosclerotic plaque formation [ 7 , 8 ], promote the proliferation of adult hippocampal dentate gyrus neural stem cells [ 9 , 10 ], and promote angiogenesis and arteriogenesis [ 11 , 12 ], and TRPV4 antagonists that treat edema, pain, gastrointestinal disorders, and pulmonary disorders [ 13 , 14 ]. In order to avoid the adverse effects of the existing TRPV4 channel drugs on patients and also to discover more effective drugs [ 15 ], high-throughput screening (HTS) of the large molecular library is necessary.…”