Functions of sensory trp channels in vascular responses to chemical and thermal stimuli

Resumen

The regulation of the blood pressure is an essential physiological process mainly regulated by the vascular tone that is dependent on the function of multiple ion channels that determine the dynamics of intracellular Ca2+ concentration in VSMC, endothelial cells, as well as in perivascular nerves. Recent studies indicate that sensory TRP channels expressed in perivascular nerves may be implicated in the mechanisms underlying arterial tone regulation through the release of many factors such as CGRP and NA due to their capacity to influence cellular excitability and intracellular Ca2+ signaling. The vascular function of these channels has been associated to their chemo- and thermosensory properties, but their actual relevance to vascular tone regulation under external stimuli remain unknown. Within the TRPM family, the role of TRPM3 channels in the contribution to vascular tone in resistance arteries has not been yet stablished. Therefore, using anatomical localization by immunofluorescence microscopy in intact resistance arteries and patch-clamp recordings in isolated VSMC, we found that TRPM3 expression in mesenteric arteries is restricted to perivascular sensory nerves. Pressure myography experiments showed that chemical activation of TRPM3 channels in mesenteric arteries by an endogenous steroid PS leads to vasodilatation, via CGRP release from perivascular sensory nerves. This data support the contribution of TRPM3 as a potential therapeutic target for the modulation of the resistance arteries tone and as a plausible effector of endogenous damage-associated molecules mediating protective responses in these vascular beds. On the other hand, sensory TRP channels have also been involved in modulating the vascular function due to their involvement in sensing environmental stimuli, being actual sensor of thermal challenges. Thus, we examine the role of sensory TRPA1 and TRPM8 channels and the underlying mechanism in a local vascular response induced by low temperatures. Using pressure myography experiments to determine changes in arterial diameter, we showed that TRPA1 and TRPM8 channels are involved in an intrinsic cold-induced vascular response in peripheral arteries and the global cold-induced potent vasoconstriction observed is the sum of the activation of these channels in sensory and sympathetic nerve endings. These results represent the first evidence for an intrinsic response to cold in cutaneous arteries and for the functional expression of TRPA1 and TRPM8 channels in efferent nerve fibers, suggesting them as the most potent targets in the treatment of cold-dependent peripheral vascular diseases. Altogether, we concluded that several sensory TRP channels play essential roles in the regulation of vascular tone in response to chemical and thermal stimuli.