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.

Development of an in vivo target‐engagement biomarker for TRPA1 antagonists in humans

“…Because TRPA1 antagonists are not yet available for human use, we were not able to test the specificity of the response to CA for TRPA1 in humans. However, extensive preclinical experiments support this specificity and currently no evidence for species differences in CA sensitivity has been reported [12,32,33]. In line with other DBF models such as the capsaicin model, one can assume that several factors such as sex, age and body site can play a role in the response to CA.…”

“…Another unresolved question is whether the DBF response observed is due to activation of neuronal and/or vascular TRPA1. Based on preclinical findings of Aubdool et al, it seems that neuronal TRPA1 is activated, which in turn causes the release of several neuropeptides including CGRP, Substance P and prostaglandins, and are most likely to play an important role in the neurogenic inflammation reaction [12,[32][33][34]. Therefore, future research questions still to be looked into are: (1) which secondary messengers are involved in the DBF response after …”

“…Consequently, activation of TRPA1 by CA results in the release of these inflammatory mediators and neuropeptides which, in turn, impact surrounding tissues including: mast cells, immune cells and vascular smooth muscle cells. The resulting response encompasses redness and warmth due to vasodilatation and hypersensitivity due to excitation of primary sensory neurons; a response which is commonly referred to as 'neurogenic inflammation' [12,13]. This makes TRPA1 a promising target for anti-inflammatory and analgesic drugs, for example for the treatment of migraine [14,15].…”

Sympathetic stimulation facilitates thrombopoiesis by promoting megakaryocyte adhesion, migration, and proplatelet formation

“…receptors. 33,34 Previous studies have demonstrated that sympathetic stimulation expands the HSC population via b2-adrenergic receptor activation, 10 whereas b3-adrenergic receptor activation triggers HSC/progenitor mobilization by decreasing stromal cellderived factor-1 (or CXC chemokine ligand 12) messenger RNA levels in BM stromal cells. 31 Activation of the b2-adrenergic receptor is involved in the isoproterenol-induced proliferation of erythroid progenitor cells, 35 whereas a1-adrenergic receptor activation mediates the stimulatory effect of noradrenergic regulation on lymphohematopoiesis.…”

High Sodium Intake Impairs Small Artery Vasoreactivity in vivo in Dahl Salt-Sensitive Rats

“…Full-field laser perfusion imaging [17] (LPI) (Moor Instruments Ltd., Devon, UK) was used to assess MSA blood perfusion by analyzing video frame rate images of blood flow. Briefly, the exposed MSAs of anesthetized rats were imaged by a two-dimensional laser speckle contrast imaging system, as mentioned above.…”