Activation of TRPM3 in Perivascular Sensory Nerves Induces Dilation of Mouse Resistance Arteries

Abstract

The vascular tone is determined by a complex interplay of vasodilator and vasoconstrictor stimuli that modulate the contractile state of vascular smooth muscle cells (VSMCs). Activation of the cation channel Transient Receptor Potential Melastatin 3 (TRPM3) has been shown to induce contraction of VSMCs in aorta. However, the contribution of this channel to the vascular tone in resistance arteries remains unknown. Real-time qPCR and immunochemistry experiments showed Trpm3 expression in mesenteric arteries isolated from wild type (WT) C57BL/6J mice. Myography experiments carried out in intact pressurized mesenteric arteries from WT mice showed that the TRPM3 agonist PS induces vasodilation at concentrations above ∼5 µM, with a concentration-dependency featuring two distinct increasing phases. In contrast, PS only induced vasodilation above 10 µM following a single Hill-type behavior in preparations from Trpm3 knockout (KO) mice. Recordings in WT arteries in the presence of the CGRP receptor antagonist BIBN 4096 recapitulated the results of Trpm3 KO preparations, indicating that the TRPM3-mediated effect of PS entails CGRP release from perivascular nerve endings. The effect of 10 µM PS was inhibited to about 50% by the combination of potassium channel blockers (500 nM paxilline, 10 µM correolide and 50 nM stromatoxin). Electrophysiological recordings in freshly isolated mesenteric VSMCs, revealed that basal currents are not sensitive to PS (10 µM and 30 µM) and that PS has no effect on potassium currents. Our data indicates that activation of TRPM3 channels in perivascular sensory nerves induces CGRP release, which leads to activation of potassium channels in smooth muscle cells, resulting in dilation of mesenteric arteries. These findings reveal a potential role of TRPM3 in vascular tone regulation, and support the recent notion that this channel may play roles in neurogenic inflammation.