Activation of the cation channel TRPM3 in perivascular nerves induces vasodilation of resistance arteries

• Published in: Journal of molecular and cellular cardiology 2019-04, Vol.129, p.219-230
• Main Authors: Alonso-Carbajo, Lucía, Alpizar, Yeranddy A., Startek, Justyna B., López-López, José Ramón, Pérez-García, María Teresa, Talavera, Karel
• Format: Article
• Language: English
• Subjects: CGRP; Perivascular nerve; Pregnenolone sulfate; TRPM3; Vasodilation
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2019.03.003

The Transient Receptor Potential Melastatin 3 (TRPM3) is a Ca2+-permeable non-selective cation channel activated by the neurosteroid pregnenolone sulfate (PS). This compound was previously shown to contract mouse aorta by activating TRPM3 in vascular smooth muscle cells (VSMC), and proposed as therapeutic modulator of vascular functions. However, PS effects and the role of TRPM3 in resistance arteries remain unknown. Thus, we aimed at determining the localization and physiological role of TRPM3 in mouse mesenteric arteries. Real-time qPCR experiments, anatomical localization using immunofluorescence microscopy and patch-clamp recordings in isolated VSMC showed that TRPM3 expression in mesenteric arteries is restricted to perivascular nerves. Pressure myography experiments in wild type (WT) mouse arteries showed that PS vasodilates with a concentration-dependence that was best fit by two Hill components (effective concentrations, EC50, of 14 and 100 μM). The low EC50 component was absent in preparations from Trpm3 knockout (KO) mice and in WT arteries in the presence of the CGRP receptor antagonist BIBN 4096. TRPM3-dependent vasodilation was partially inhibited by a cocktail of K+ channel blockers, and not mediated by β-adrenergic signaling. We conclude that, contrary to what was found in aorta, PS dilates mesenteric arteries, partly via an activation of TRPM3 that triggers CGRP release from perivascular nerve endings and a subsequent activation of K+ channels in VSMC. We propose that TRPM3 is implicated in the regulation of the tone of resistance arteries and that its activation by yet unidentified endogenous damage-associated molecules lead to protective vasodilation responses in mesenteric arteries. [Display omitted] •TRPM3 expression is restricted to sensory nerve endings in mesenteric arteries.•TRPM3 activation dilates mesenteric arteries via CGRP release from nerve endings.•Pregnenolone sulfate is a specific TRPM3 aganist at concentrations below 10 μM.•TRPM3-mediated vasodilation is partly driven by activation of KV channels in VSMC.•Endogenous TRPM3 agonists can contribute to vascular tone regulation.