Dysfunctional TRPM8 signalling in the vascular response to environmental cold in ageing

  1. Dibesh Thapa
  2. Joäo de Sousa Valente
  3. Brentton Barrett
  4. Matthew John Smith
  5. Fulye Argunhan
  6. Sheng Y Lee
  7. Sofya Nikitochkina
  8. Xenia Kodji
  9. Susan D Brain  Is a corresponding author
  1. King's College London, United Kingdom
  2. University of Cambridge, United Kingdom
  3. Agency for Science, Technology and Research (A*STAR), Singapore

Abstract

Ageing is associated with increased vulnerability to environmental cold exposure. Previously, we identified the role of the cold-sensitive transient receptor potential (TRP) A1, M8 receptors as vascular cold sensors in mouse skin. We hypothesised that this dynamic cold-sensor system may become dysfunctional in ageing. We show that behavioural and vascular responses to skin local environmental cooling are impaired with even moderate ageing, with reduced TRPM8 gene/protein expression especially. Pharmacological blockade of the residual TRPA1/TRPM8 component substantially diminished the response in aged, compared with young mice. This implies the reliance of the already reduced cold-induced vascular response in ageing mice on remaining TRP receptor activity. Moreover, sympathetic-induced vasoconstriction was reduced with downregulation of the α2c adrenoceptor expression in ageing. The cold-induced vascular response is important for sensing cold and retaining body heat and health. These findings reveal that cold sensors, essential for this neurovascular pathway, decline as ageing onsets.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. The source data file with original uncropped western blot images have been uploaded (The blots are labelled as they are in the manuscript). Source data excel file containing raw data for blood flow graphs has also been uploaded which was used for graphical analysis in the main manuscript.

Article and author information

Author details

  1. Dibesh Thapa

    King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7435-5483
  2. Joäo de Sousa Valente

    King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Brentton Barrett

    King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Matthew John Smith

    King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Fulye Argunhan

    King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Sheng Y Lee

    University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Sofya Nikitochkina

    King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Xenia Kodji

    Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  9. Susan D Brain

    King's College London, London, United Kingdom
    For correspondence
    sue.brain@kcl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9684-8342

Funding

Biotechnology and Biological Sciences Research Council (BB/P005616/1)

  • Dibesh Thapa

Versus Arthritis (ARUK21524)

  • Joäo de Sousa Valente

British Heart Foundation (FS/19/42/34527)

  • Brentton Barrett

British Heart Foundation (PG/12/34/29557)

  • Fulye Argunhan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were performed according to the Animal Care and Ethics committee at King's College London, in addition to the regulations set by the UK home office Animals (Scientific Procedures) act 1986. The protocol was approved by UK home office under license number P2C5FC8CF. Experiments using animals were designed and reported in line with the ARRIVE guidelines, which form the NC3Rs initiative.

Reviewing Editor

  1. Arduino A Mangoni, Flinders Medical Centre, Australia

Publication history

  1. Received: May 7, 2021
  2. Preprint posted: May 10, 2021 (view preprint)
  3. Accepted: November 2, 2021
  4. Accepted Manuscript published: November 2, 2021 (version 1)
  5. Version of Record published: November 15, 2021 (version 2)

Copyright

© 2021, Thapa et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Dibesh Thapa
  2. Joäo de Sousa Valente
  3. Brentton Barrett
  4. Matthew John Smith
  5. Fulye Argunhan
  6. Sheng Y Lee
  7. Sofya Nikitochkina
  8. Xenia Kodji
  9. Susan D Brain
(2021)
Dysfunctional TRPM8 signalling in the vascular response to environmental cold in ageing
eLife 10:e70153.
https://doi.org/10.7554/eLife.70153
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