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

Research output: Contribution to journalArticle

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.

LanguageEnglish
Pages3297-3317
Number of pages21
JournalBritish Journal of Pharmacology
Volume176
Issue number17
Early online date8 Jun 2019
DOIs
Publication statusPublished - 30 Sep 2019

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Inositol 1,4,5-Trisphosphate Receptors
Blood Vessels
Endothelium
Ion Channels
Cations
Endothelial Cells
Arteries

Keywords

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

Cite this

@article{a7823f81f0b14eee8ade8c7ba2eacf5c,
title = "Endothelial TRPV4 channels modulate vascular tone by Ca 2+-induced Ca 2+ release at inositol 1,4,5-trisphosphate receptors",
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.",
keywords = "vascular, endothelium, calcium, transient receptor potential channels (TRP channels), inositol 1,4,5‐trisphosphate (IP3), GSK1016790A, Ca2+-induced Ca2+ release, TRPV4",
author = "Heathcote, {Helen R.} and Lee, {Matthew D.} and Xun Zhang and Saunter, {Christopher D.} and Calum Wilson and McCarron, {John G.}",
year = "2019",
month = "9",
day = "30",
doi = "10.1111/bph.14762",
language = "English",
volume = "176",
pages = "3297--3317",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
number = "17",

}

TY - JOUR

T1 - Endothelial TRPV4 channels modulate vascular tone by Ca 2+-induced Ca 2+ release at inositol 1,4,5-trisphosphate receptors

AU - Heathcote, Helen R.

AU - Lee, Matthew D.

AU - Zhang, Xun

AU - Saunter, Christopher D.

AU - Wilson, Calum

AU - McCarron, John G.

PY - 2019/9/30

Y1 - 2019/9/30

N2 - 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.

AB - 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.

KW - vascular

KW - endothelium

KW - calcium

KW - transient receptor potential channels (TRP channels)

KW - inositol 1,4,5‐trisphosphate (IP3)

KW - GSK1016790A

KW - Ca2+-induced Ca2+ release

KW - TRPV4

UR - https://bpspubs.onlinelibrary.wiley.com/journal/14765381

U2 - 10.1111/bph.14762

DO - 10.1111/bph.14762

M3 - Article

VL - 176

SP - 3297

EP - 3317

JO - British Journal of Pharmacology

T2 - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 17

ER -