Heteromeric TRPV4/TRPC1 channels mediate calcium-sensing receptor-induced relaxations and nitric oxide production in mesenteric arteries: comparative study using wild-type and TRPC1-/- mice.
Heteromeric TRPV4/TRPC1 channels mediate calcium-sensing receptor-induced relaxations and nitric oxide production in mesenteric arteries: comparative study using wild-type and TRPC1-/- mice.
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DOI：
10.1080/19336950.2019.1673131
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发表时间：
2019-12-01
期刊：
影响因子：
--
通讯作者：
Albert, Anthony P
中科院分区：
文献类型：
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作者：
Greenberg, Harry Z E;Carlton-Carew, Simonette R E;Albert, Anthony P
我们以前提供的药理学证据表明，钙敏感受体（CaSR）的刺激诱导内皮依赖性舒张兔肠系膜动脉通过激活异聚体TRPV 4/TRPC 1通道和一氧化氮（NO）的生产。本研究通过比较野生型（WT）和TRPC 1-/-小鼠肠系膜动脉中的反应，进一步研究了异聚TRPV 4/TRPC 1通道在这些CaSR诱导的血管反应中的作用。在WT小鼠中，CaSR的刺激诱导内皮细胞（EC）中的预收缩张力和NO产生的内皮依赖性舒张，这被TRPV 4通道阻断剂RN 1734和TRPC 1阻断抗体T1 E3抑制。此外，TRPV 4和TRPC 1蛋白共定位于或接近WT小鼠内皮细胞（EC）的质膜。相反，在TRPC 1-/-小鼠中，CaSR介导的血管舒张和NO生成大大减少，不受T1 E3的影响，但被RN 1734阻断。此外，TRPV 4激动剂GSK 1016790 A（GSK）诱导内皮依赖性血管舒张，在WT小鼠中，这种舒张被RN 1734和T1 E3阻断，但在TRPC 1-/-小鼠中仅被RN 1734阻断。此外，GSK激活阳离子通道活性，在WT EC中具有6pS电导，而在TRPC 1-/-EC中具有52 pS电导。这些结果表明，CaSR的刺激激活异聚TRPV 4/TRPC 1通道和NO的产生在EC中，这是负责内皮依赖性血管舒张。这项研究还表明，异聚体TRPV 4-TRPC 1通道可能形成小鼠肠系膜动脉EC中主要的TRPV 4通道。总之，我们的数据进一步暗示了CaSR诱导的途径和异聚TRPV 4/TRPC 1通道在调节血管张力中的作用。
We have previously provided pharmacological evidence that stimulation of calcium-sensing receptors (CaSR) induces endothelium-dependent relaxations of rabbit mesenteric arteries through activation of heteromeric TRPV4/TRPC1 channels and nitric oxide (NO) production. The present study further investigates the role of heteromeric TRPV4/TRPC1 channels in these CaSR-induced vascular responses by comparing responses in mesenteric arteries from wild-type (WT) and TRPC1-/- mice. In WT mice, stimulation of CaSR induced endothelium-dependent relaxations of pre-contracted tone and NO generation in endothelial cells (ECs), which were inhibited by the TRPV4 channel blocker RN1734 and the TRPC1 blocking antibody T1E3. In addition, TRPV4 and TRPC1 proteins were colocalised at, or close to, the plasma membrane of endothelial cells (ECs) from WT mice. In contrast, in TRPC1-/- mice, CaSR-mediated vasorelaxations and NO generation were greatly reduced, unaffected by T1E3, but blocked by RN1734. In addition, the TRPV4 agonist GSK1016790A (GSK) induced endothelium-dependent vasorelaxations which were blocked by RN1734 and T1E3 in WT mice, but only by RN1734 in TRPC1-/- mice. Moreover, GSK activated cation channel activity with a 6pS conductance in WT ECs but with a 52 pS conductance in TRPC1-/- ECs. These results indicate that stimulation of CaSR activates heteromeric TRPV4/TRPC1 channels and NO production in ECs, which are responsible for endothelium-dependent vasorelaxations. This study also suggests that heteromeric TRPV4-TRPC1 channels may form the predominant TRPV4-containing channels in mouse mesenteric artery ECs. Together, our data further implicates CaSR-induced pathways and heteromeric TRPV4/TRPC1 channels in the regulation of vascular tone.