Abstract
The cold-induced vascular response, consisting of vasoconstriction followed by vasodilatation, is critical for protecting the cutaneous tissues against cold injury. Whilst this physiological reflex response is historic knowledge, the mechanisms involved are unclear. Here by using a murine model of local environmental cold exposure, we show that TRPA1 acts as a primary vascular cold sensor, as determined through TRPA1 pharmacological antagonism or gene deletion. The initial cold-induced vasoconstriction is mediated via TRPA1-dependent superoxide production that stimulates α2C-adrenoceptors and Rho-kinase-mediated MLC phosphorylation, downstream of TRPA1 activation. The subsequent restorative blood flow component is also dependent on TRPA1 activation being mediated by sensory nerve-derived dilator neuropeptides CGRP and substance P, and also nNOS-derived NO. The results allow a new understanding of the importance of TRPA1 in cold exposure and provide impetus for further research into developing therapeutic agents aimed at the local protection of the skin in disease and adverse climates.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acetanilides / pharmacology
-
Animals
-
Calcitonin Gene-Related Peptide / genetics
-
Calcitonin Gene-Related Peptide / metabolism
-
Cold Temperature / adverse effects
-
Gene Expression Regulation
-
Hindlimb
-
Hypothermia / etiology
-
Hypothermia / genetics
-
Hypothermia / metabolism*
-
Hypothermia / pathology
-
Male
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism
-
Mice
-
Mice, Knockout
-
Nitric Oxide / biosynthesis
-
Nitric Oxide Synthase Type I / genetics
-
Nitric Oxide Synthase Type I / metabolism
-
Phosphorylation
-
Purines / pharmacology
-
Receptors, Adrenergic, alpha / genetics*
-
Receptors, Adrenergic, alpha / metabolism
-
Signal Transduction
-
Skin / blood supply*
-
Skin / metabolism
-
Skin / pathology
-
Substance P / genetics
-
Substance P / metabolism
-
Superoxides / metabolism
-
TRPA1 Cation Channel
-
Transient Receptor Potential Channels / antagonists & inhibitors
-
Transient Receptor Potential Channels / deficiency
-
Transient Receptor Potential Channels / genetics*
-
Vasoconstriction / genetics*
-
Vasodilation / genetics
-
rho-Associated Kinases / genetics
-
rho-Associated Kinases / metabolism
Substances
-
2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide
-
Acetanilides
-
Membrane Proteins
-
Mlc1 protein, mouse
-
Purines
-
Receptors, Adrenergic, alpha
-
TRPA1 Cation Channel
-
Transient Receptor Potential Channels
-
Trpa1 protein, mouse
-
Superoxides
-
Nitric Oxide
-
Substance P
-
Nitric Oxide Synthase Type I
-
Nos1 protein, mouse
-
rho-Associated Kinases
-
Calcitonin Gene-Related Peptide