TRPA1 is essential for the vascular response to environmental cold exposure

• Published in: Nature communications 2014-12, Vol.5 (1), p.5732, Article 5732
• Main Authors: Aubdool, Aisah A., Graepel, Rabea, Kodji, Xenia, Alawi, Khadija M., Bodkin, Jennifer V., Srivastava, Salil, Gentry, Clive, Heads, Richard, Grant, Andrew D., Fernandes, Elizabeth S., Bevan, Stuart, Brain, Susan D.
• Format: Article
• Language: English
• Subjects: 59; 631/443; 64; 64/110; 692/308; 82; Acetanilides - pharmacology; Animals; Calcitonin Gene-Related Peptide - genetics; Calcitonin Gene-Related Peptide - metabolism; Cold Temperature - adverse effects; Gene Expression Regulation; Hindlimb; Humanities and Social Sciences; Hypothermia - etiology; Hypothermia - genetics; Hypothermia - metabolism; Hypothermia - pathology; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; multidisciplinary; 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; rho-Associated Kinases - genetics; rho-Associated Kinases - metabolism; Science; Science (multidisciplinary); Signal Transduction; Skin - blood supply; Skin - metabolism; Skin - pathology; Substance P - genetics; Substance P - metabolism; Superoxides - metabolism; Transient Receptor Potential Channels - antagonists & inhibitors; Transient Receptor Potential Channels - deficiency; Transient Receptor Potential Channels - genetics; TRPA1 Cation Channel; Vasoconstriction - genetics; Vasodilation - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms6732

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 α 2C -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. Blood flow in the skin of mammals changes in response to cold, but the mechanisms driving this response are unclear. Aubdool et al . show that the non-selective cation channel, TRPA1, is a vascular cold sensor and required for the vascular protective response to local cold exposure.