Endothelial TRPV4 channels modulate vascular tone by Ca(2+)‐induced Ca(2+) release at inositol 1,4,5‐trisphosphate receptors

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.