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

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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.

Original languageEnglish
Pages (from-to)3297-3317
Number of pages21
JournalBritish Journal of Pharmacology
Volume176
Issue number17
Early online date8 Jun 2019
DOIs
Publication statusPublished - 30 Sep 2019

Keywords

  • vascular
  • endothelium
  • calcium
  • transient receptor potential channels (TRP channels)
  • inositol 1,4,5‐trisphosphate (IP3)
  • GSK1016790A
  • Ca2+-induced Ca2+ release
  • TRPV4

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