Endothelial TRPV4 channels modulate vascular tone by Ca²⁺‐induced Ca²⁺ release at inositol 1,4,5‐trisphosphate receptors

Abstract

Background and Purpose The TRPV4 ion channels are Ca 2+ permeable, non‐selective cation channels that mediate large, but highly localized, Ca 2+ signals in the endothelium. The mechanisms that permit highly localized Ca 2+ changes to evoke cell‐wide activity are incompletely understood. Here, we tested the hypothesis that TRPV4‐mediated Ca 2+ influx activates Ca 2+ release from internal Ca 2+ stores to generate widespread effects. Experimental Approach Ca 2+ signals in large numbers (~100) of endothelial cells in intact arteries were imaged and analysed separately. Key Results Responses to the TRPV4 channel agonist GSK1016790A were heterogeneous across the endothelium. In activated cells, Ca 2+ responses comprised localized Ca 2+ changes leading to slow, persistent, global increases in Ca 2+ followed by large propagating Ca 2+ waves that moved within and between cells. To examine the mechanisms underlying each component, we developed methods to separate slow persistent Ca 2+ rise from the propagating Ca 2+ waves in each cell. TRPV4‐mediated Ca 2+ entry was required for the slow persistent global rise and propagating Ca 2+ signals. The propagating waves were inhibited by depleting internal Ca 2+ stores, inhibiting PLC or blocking IP 3 receptors. Ca 2+ release from stores was tightly controlled by TRPV4‐mediated Ca 2+ influx and ceased when influx was terminated. Furthermore, Ca 2+ release from internal stores was essential for TRPV4‐mediated control of vascular tone. Conclusions and Implications Ca 2+ influx via TRPV4 channels is amplified by Ca 2+ ‐induced Ca 2+ release acting at IP 3 receptors to generate propagating Ca 2+ waves and provide a large‐scale endothelial communication system. TRPV4‐mediated control of vascular tone requires Ca 2+ release from the internal store.

Mechanisms underlying selective coupling of endothelial Ca2+ signals with eNOS vs. IK/SK channels in systemic and pulmonary arteries

“…Multiple ion channels increase Ca 2+ levels in native ECs, including ion channels of the transient receptor potential (TRP) family (Earley et al 2009;Sonkusare et al 2012;Pires et al 2015;Sullivan et al 2015;Hong et al 2018) and inositol triphosphate receptors (Ledoux et al 2008b;McCarron et al 2010;Bagher et al 2012;Tran et al 2012;Heathcote et al 2019). The TRP vanilloid 4 (TRPV4) channel has emerged as an important Ca 2+ -influx pathway in ECs from systemic and pulmonary resistance arteries (Bagher et al 2012;Sonkusare et al 2014;Marziano et al 2017;Hong et al 2018).…”

Pacemaker function and neural responsiveness of subserosal interstitial cells of Cajal in the mouse colon

“…Recently, the efficacy of XeC as a selective inhibitor of IP 3 Rs has been questioned (Saleem et al 2014) and off target effects other than IP 3 R inhibition have been reported for this agent (Sergeant et al 2001). Experiments performed on isolated isoforms of the IP 3 R (IP 3 R1-3) in expressed systems and on IP 3 R-dependent Ca 2+ signalling in vascular endothelial cells have demonstrated that caffeine is an effective antagonist of IP 3 R1 (dominant isoform in ICC) (Baker et al 2016;Drumm et al 2017Drumm et al , 2019b at concentrations of 10 mM (Saleem et al 2014;Heathcote et al 2019). Although caffeine is also known to be a modulator of RyRs, the lack of effect of the RyR antagonist on ICC-SS Ca 2+ signals ( Fig.…”

Disrupted Endothelial Cell Heterogeneity and Network Organization Impairs Vascular Function in Prediabetic Obesity

“…We next examined the relationship between spontaneous Ca 2+ activity and IEL holes ( Figure S10 and Table S8). In contrast to ACh-evoked Ca 2+ activity, basal (unstimulated) Ca 2+ events are mostly subcellular waves and the initiation site of individual events can be readily identified (see also 29,32 ). Importantly, irrespective of diet, we found that endothelial Ca 2+ events occurred closer to MEPs than would be expected than if they occurred randomly throughout the cytoplasm ( Figure S10C-D and Table S8).…”