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

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Heathcote, Helen R. and Lee, Matthew D. and Zhang, Xun and Saunter, Christopher D. and Wilson, Calum and McCarron, John G. (2019) Endothelial TRPV4 channels modulate vascular tone by Ca 2+-induced Ca 2+ release at inositol 1,4,5-trisphosphate receptors. British Journal of Pharmacology, 176 (17). pp. 3297-3317. ISSN 1476-5381 (https://doi.org/10.1111/bph.14762)

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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.

ORCID iDs

Heathcote, Helen R., Lee, Matthew D. ORCID logoORCID: https://orcid.org/0000-0001-8265-382X, Zhang, Xun ORCID logoORCID: https://orcid.org/0000-0003-0790-4291, Saunter, Christopher D., Wilson, Calum ORCID logoORCID: https://orcid.org/0000-0003-2500-0632 and McCarron, John G. ORCID logoORCID: https://orcid.org/0000-0002-3302-3984;
CORE (COnnecting REpositories)