Figure 5: The cold-induced vascular response is dependent on neuropeptides.
From: TRPA1 is essential for the vascular response to environmental cold exposure
Blood flow was measured using FLPI in anaesthetized mice following immersion of the ipsilateral hindpaw in cold (10 °C) water and the contralateral hindpaw remained untreated. Mice were pretreated with pharmacological inhibitors or the respective vehicle (i.v., 5 min) before local cold exposure. (a) Effects of CGRP receptor antagonist CGRP8–37 (400 nmol kg−1, n=7) on the cold-induced vascular response in WT mice. (b) Cold-induced vascular response in WT mice pretreated with a combination of CGRP8–37 and NK1 receptor antagonist SR140333 (480 nmol kg−1, n=8) with or without the non-selective NOS inhibitor L-NAME (15 mg kg−1, n=7) and control (0.01% BSA in saline, n=10). (c) Effects of CGRP8–37, SR140333 and the selective nNOS inhibitor SMTC (10 mg kg−1, n=6) or control (0.01% BSA in saline, n=7) on the cold-induced vascular response in WT mice. All error bars indicate s.e.m. *P<0.05, ***P<0.001, ****P<0.0001 versus respective untreated, ###P<0.001, ####P<0.0001 versus cold-treated hindpaw (analysis of variance, Bonferroni post hoc test). (d) Proposed cold-induced TRPA1 pathway in the regulation of cutaneous vasculature. Local cold exposure (10 °C) causes a transient and rapid decrease in blood flow from baseline (1). This initial phase of cold-induced vasoconstriction consists of activation of TRPA1 which further mediates to (a) the release of noradrenaline (NA) and (b) increased reactive oxygen species release (for example, superoxide (O2−) generation) that can also activate the ROCK-mediated pathways and increase constriction via phosphorylated MLC-induced increase in [Ca2+]i. The O2− induces the translocation of α2C-adrenoceptors from the Golgi to the surface membrane and increases adrenergic activity in the VSMC in a ROCK-dependent fashion25. (2) The restoration of blood flow following local cold treatment is essential in restoring blood flow to baseline to protect against local cold-induced injuries. This phase is mediated by the release of CGRP, substance P and nitric oxide following TRPA1 activation of sensory neurons. MLC-P, myosin light chain phosphatase; NA, noradrenaline; p-MLC; phosphorylated myosin light chain; VSMC, vascular smooth muscle cell.
