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

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

Abstract

Background and Purpose: The TRPV4 ion channels are Ca2+ permeable, non‐selective 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 internal Ca2+ stores 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: Responses to the TRPV4 channel agonist GSK1016790A were heterogeneous across the endothelium. In activated cells, Ca2+ responses comprised localized Ca2+ changes leading to slow, persistent, global increases 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 internal Ca2+ stores, inhibiting PLC or blocking IP3 receptors. Ca2+ release from stores was tightly controlled by TRPV4‐mediated Ca2+ influx and ceased when influx was terminated. Furthermore, Ca2+ release from internal stores was essential for TRPV4‐mediated control of vascular tone. Conclusions and Implications: Ca2+ influx via TRPV4 channels 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.

Citation

Heathcote, H. R., Lee, M. D., Zhang, X., Saunter, C. D., Wilson, C., & McCarron, J. G. (2019). Endothelial TRPV4 channels modulate vascular tone by Ca2+‐induced Ca2+ release at inositol 1,4,5‐trisphosphate receptors. British Journal of Pharmacology, 176(17), 3297-3317. https://doi.org/10.1111/bph.14762

• Journal Article Type: Article
• Acceptance Date: May 20, 2019
• Online Publication Date: Jul 24, 2019
• Publication Date: Sep 1, 2019
• Deposit Date: Aug 8, 2019
• Publicly Available Date: Aug 8, 2019
• Journal: British Journal of Pharmacology
• Print ISSN: 0007-1188
• Electronic ISSN: 1476-5381
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 176
• Issue: 17
• Pages: 3297-3317
• DOI: https://doi.org/10.1111/bph.14762
• Public URL: https://durham-repository.worktribe.com/output/1325736