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

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Dibesh Thapa, Joao Sousa-Valente, Brentton Barrett, Matthew Smith, Fulye Argunhan, Sheng Y Lee, Sofya Nikitochkina , Xenia Kodji, Susan Brain

Original languageEnglish
Article numbere70153
Early online date2 Nov 2021
Accepted/In press2 Nov 2021
E-pub ahead of print2 Nov 2021
PublishedNov 2021

Bibliographical note

Funding Information: This work was primarily funded by BBSRC (BB/P005616/1). It was also supported in part by Versus Arthritis (ARUK21524) and British Heart Foundation (BHF-FS/19/42/34527 and PG/12/34/29557). We thank Professor Giovanni Mann for academic input concerning the calcium imaging experiments. Publisher Copyright: ‍© Thapa et al.


King's Authors


Ageing is associated with increased vulnerability to environmental cold exposure. Previ-ously, 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 α 2c adre-noceptor 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 neuro-vascular pathway, decline as ageing onsets.

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