title: TRPA1 is essential for the vascular response to environmental cold exposure.
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.
authors.affiliation: BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, Cardiovascular Division, King's College London, London SE1 9NH, UK.
authors.forename: Aisah A
authors.initials: AA
authors.lastname: Aubdool
authors.affiliation: BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, Cardiovascular Division, King's College London, London SE1 9NH, UK.
authors.forename: Rabea
authors.initials: R
authors.lastname: Graepel
authors.affiliation: BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, Cardiovascular Division, King's College London, London SE1 9NH, UK.
authors.forename: Xenia
authors.initials: X
authors.lastname: Kodji
authors.affiliation: BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, Cardiovascular Division, King's College London, London SE1 9NH, UK.
authors.forename: Khadija M
authors.initials: KM
authors.lastname: Alawi
authors.affiliation: BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, Cardiovascular Division, King's College London, London SE1 9NH, UK.
authors.forename: Jennifer V
authors.initials: JV
authors.lastname: Bodkin
authors.affiliation: BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, Cardiovascular Division, King's College London, London SE1 9NH, UK.
authors.forename: Salil
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Wolfson Centre for Age Related Diseases, King's College London, London SE1 1UL, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: Gentry
authors.affiliation: BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, Cardiovascular Division, King's College London, London SE1 9NH, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Heads
authors.affiliation: Wolfson Centre for Age Related Diseases, King's College London, London SE1 1UL, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Grant
authors.affiliation: BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, Cardiovascular Division, King's College London, London SE1 9NH, UK.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Fernandes
authors.affiliation: Wolfson Centre for Age Related Diseases, King's College London, London SE1 1UL, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Bevan
authors.affiliation: BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, Cardiovascular Division, King's College London, London SE1 9NH, UK.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Brain
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism; D003080:Cold Temperature / Q000009:adverse effects; D005786:Gene Expression Regulation; D006614:Hindlimb; D007035:Hypothermia / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011687:Purines / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D013373:Substance P / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D014661:Vasoconstriction / Q000235:genetics*; D014664:Vasodilation / Q000235:genetics; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; D008565:Membrane Proteins; C498927:Mlc1 protein, mouse; D011687:Purines; D011942:Receptors, Adrenergic, alpha; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D013481:Superoxides; D009569:Nitric Oxide; D013373:Substance P; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D054460:rho-Associated Kinases; D015740:Calcitonin Gene-Related Peptide