Activation of the cation channel TRPM3 in perivascular nerves induces vasodilation of resistance arteries
Activation of the cation channel TRPM3 in perivascular nerves induces vasodilation of resistance arteries
复制标题
DOI：
10.1016/j.yjmcc.2019.03.003
复制
发表时间：
2019-04-01
影响因子：
5
通讯作者：
Talavera, Karel
中科院分区：
文献类型：
--
作者：
Alonso-Carbajo, Lucia;Alpizar, Yeranddy A.;Talavera, Karel
瞬时受体电位Melastatin 3（TRPM 3）是由神经类固醇硫酸双烯醇酮（PS）激活的Ca 2+可渗透的非选择性阳离子通道。该化合物先前显示通过激活血管平滑肌细胞（VSMC）中的TRPM 3来收缩小鼠主动脉，并被提议作为血管功能的治疗性调节剂。然而，PS的影响和TRPM 3在阻力动脉中的作用仍然未知。因此，我们旨在确定TRPM 3在小鼠肠系膜动脉中的定位和生理作用。实时qPCR实验、使用免疫荧光显微镜和膜片钳记录在分离的VSMC中的解剖定位表明，TRPM 3在肠系膜动脉中的表达仅限于血管周围神经。压力肌电图实验在野生型（WT）小鼠动脉显示，PS血管舒张与浓度依赖性，最适合由两个希尔组件（有效浓度，EC 50，14和100 μ M）。Trpm 3敲除（KO）小鼠的制备物和存在CGRP受体拮抗剂BIBN 4096的WT动脉中不存在低EC 50组分。TRPM 3依赖性血管舒张被K+通道阻滞剂的混合物部分抑制，而不是由β-肾上腺素能信号传导介导的。我们的结论是，相反，在主动脉中发现，PS扩张肠系膜动脉，部分通过激活TRPM 3，触发CGRP释放血管周围神经末梢和随后激活的K+通道VSMC。我们认为TRPM 3参与了阻力动脉张力的调节，并且其被尚未鉴定的内源性损伤相关分子激活导致肠系膜动脉中的保护性血管舒张反应。
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 mu M). 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 beta-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.