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Title: Endothelial TRPV4 channels modulate vascular tone by Ca²⁺ -induced Ca²⁺ release at inositol 1,4,5-trisphosphate receptors.
Author: Heathcote HR, Lee MD, Zhang X, Saunter CD, Wilson C, McCarron JG.
Journal: Br J Pharmacol; 2019 Sep; 176(17):3297-3317. PubMed ID: 31177523.
Abstract:
BACKGROUND AND PURPOSE: The TRPV4 ion channels are Ca²⁺ permeable, non-selective cation channels that mediate large, but highly localized, Ca²⁺ signals in the endothelium. The mechanisms that permit highly localized Ca²⁺ changes to evoke cell-wide activity are incompletely understood. Here, we tested the hypothesis that TRPV4-mediated Ca²⁺ influx activates Ca²⁺ release from internal Ca²⁺ stores to generate widespread effects. EXPERIMENTAL APPROACH: Ca²⁺ 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, Ca²⁺ responses comprised localized Ca²⁺ changes leading to slow, persistent, global increases in Ca²⁺ followed by large propagating Ca²⁺ waves that moved within and between cells. To examine the mechanisms underlying each component, we developed methods to separate slow persistent Ca²⁺ rise from the propagating Ca²⁺ waves in each cell. TRPV4-mediated Ca²⁺ entry was required for the slow persistent global rise and propagating Ca²⁺ signals. The propagating waves were inhibited by depleting internal Ca²⁺ stores, inhibiting PLC or blocking IP₃ receptors. Ca²⁺ release from stores was tightly controlled by TRPV4-mediated Ca²⁺ influx and ceased when influx was terminated. Furthermore, Ca²⁺ release from internal stores was essential for TRPV4-mediated control of vascular tone. CONCLUSIONS AND IMPLICATIONS: Ca²⁺ influx via TRPV4 channels is amplified by Ca²⁺ -induced Ca²⁺ release acting at IP₃ receptors to generate propagating Ca²⁺ waves and provide a large-scale endothelial communication system. TRPV4-mediated control of vascular tone requires Ca²⁺ release from the internal store.

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