Endothelial TRPV4 channels modulate vascular tone by Ca2+-induced Ca2+ release at IP3 receptors : endothelial TRPV4 activation induces IP3-mediated Ca2+ release

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 Ca2+-induced Ca2+ release at IP3 receptors : endothelial TRPV4 activation induces IP3-mediated Ca2+ release. British Journal of Pharmacology. ISSN 1476-5381

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    Abstract

    Background and Purpose. Transient receptor potential vanilloid 4 (TRPV4) channels are Ca2+-permeable, nonselective 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 the internal Ca2+ store 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. The response to pharmacological TRPV4 activation (GSK1016790A) was heterogeneous across the endothelium. In those cells activated, the Ca2+ response consisted of localized Ca2+ changes that led to a slow persistent global rise 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 the internal Ca2+ store, inhibiting phospholipase C or blocking IP3 receptors. Ca2+ release from the store was tightly-controlled by TRPV4-mediated Ca2+ influx and ceased when influx was terminated. Furthermore, Ca2+ release from the internal store was essential for TRPV4-mediated control of vascular tone. Conclusion and Implications. Ca2+ influx via TRPV4 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.