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Heathcote, Helen R.; Lee, Matthew D.; Zhang, Xun; Saunter, Christopher D.; Wilson, Calum; McCarron, John G.

Endothelial TRPV4 channels modulate vascular tone by Ca2+‐induced Ca2+ release at inositol 1,4,5‐trisphosphate receptors

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  • Medientyp: E-Artikel
  • Titel: Endothelial TRPV4 channels modulate vascular tone by Ca2+‐induced Ca2+ release at inositol 1,4,5‐trisphosphate receptors
  • Beteiligte: Heathcote, Helen R.; Lee, Matthew D.; Zhang, Xun; Saunter, Christopher D.; Wilson, Calum; McCarron, John G.
  • Erschienen: Wiley, 2019
  • Erschienen in: British Journal of Pharmacology
  • Sprache: Englisch
  • DOI: 10.1111/bph.14762
  • ISSN: 0007-1188; 1476-5381
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:sec><jats:title>Background and Purpose</jats:title><jats:p>The TRPV4 ion channels are Ca<jats:sup>2+</jats:sup> permeable, non‐selective cation channels that mediate large, but highly localized, Ca<jats:sup>2+</jats:sup> signals in the endothelium. The mechanisms that permit highly localized Ca<jats:sup>2+</jats:sup> changes to evoke cell‐wide activity are incompletely understood. Here, we tested the hypothesis that TRPV4‐mediated Ca<jats:sup>2+</jats:sup> influx activates Ca<jats:sup>2+</jats:sup> release from internal Ca<jats:sup>2+</jats:sup> stores to generate widespread effects.</jats:p></jats:sec><jats:sec><jats:title>Experimental Approach</jats:title><jats:p>Ca<jats:sup>2+</jats:sup> signals in large numbers (~100) of endothelial cells in intact arteries were imaged and analysed separately.</jats:p></jats:sec><jats:sec><jats:title>Key Results</jats:title><jats:p>Responses to the TRPV4 channel agonist GSK1016790A were heterogeneous across the endothelium. In activated cells, Ca<jats:sup>2+</jats:sup> responses comprised localized Ca<jats:sup>2+</jats:sup> changes leading to slow, persistent, global increases in Ca<jats:sup>2+</jats:sup> followed by large propagating Ca<jats:sup>2+</jats:sup> waves that moved within and between cells. To examine the mechanisms underlying each component, we developed methods to separate slow persistent Ca<jats:sup>2+</jats:sup> rise from the propagating Ca<jats:sup>2+</jats:sup> waves in each cell. TRPV4‐mediated Ca<jats:sup>2+</jats:sup> entry was required for the slow persistent global rise and propagating Ca<jats:sup>2+</jats:sup> signals. The propagating waves were inhibited by depleting internal Ca<jats:sup>2+</jats:sup> stores, inhibiting PLC or blocking IP<jats:sub>3</jats:sub> receptors. Ca<jats:sup>2+</jats:sup> release from stores was tightly controlled by TRPV4‐mediated Ca<jats:sup>2+</jats:sup> influx and ceased when influx was terminated. Furthermore, Ca<jats:sup>2+</jats:sup> release from internal stores was essential for TRPV4‐mediated control of vascular tone.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Implications</jats:title><jats:p>Ca<jats:sup>2+</jats:sup> influx via TRPV4 channels is amplified by Ca<jats:sup>2+</jats:sup>‐induced Ca<jats:sup>2+</jats:sup> release acting at IP<jats:sub>3</jats:sub> receptors to generate propagating Ca<jats:sup>2+</jats:sup> waves and provide a large‐scale endothelial communication system. TRPV4‐mediated control of vascular tone requires Ca<jats:sup>2+</jats:sup> release from the internal store.</jats:p></jats:sec>
  • Zugangsstatus: Freier Zugang