Dysfunctional TRPM8 signalling in the vascular response to environmental cold in ageing
- King's College London, United Kingdom
- University of Cambridge, United Kingdom
- 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
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.
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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Dysfunctional TRPM8 signalling in the vascular response to environmental cold in ageing
eLife 10:e70153.
https://doi.org/10.7554/eLife.70153
