A TRPC3/6 Channel Inhibitor Promotes Arteriogenesis after Hind-Limb Ischemia.
A TRPC3/6 Channel Inhibitor Promotes Arteriogenesis after Hind-Limb Ischemia.
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大电导动脉进展性闭塞后血运重建延迟是外周动脉疾病（PAD）预后不良的主要原因。然而，PAD的药物治疗仍然有限。我们以前报道，抑制瞬时受体电位典型（TRPC）6通道活动在血管平滑肌细胞（VSMCs）促进VSMC分化，而不影响增殖和迁移。在这项研究中，我们发现，1-benzilpiperadine衍生物（1-BP），一个选择性抑制剂的TRPC 3和TRPC 6通道活动，诱导VSMC分化。1-BP处理的小鼠在小鼠后肢缺血（HLI）后表现出增加的毛细血管动脉化和外周循环和骨骼肌质量的改善。1-BP对TRPC 6缺陷小鼠HLI后血流恢复的促进作用没有累加效应，表明TRPC 6的抑制是1-BP促进血流恢复的基础。1-BP还改善了血管内皮功能障碍的高胆固醇血症小鼠HLI后血管一氧化氮的生物利用度和血流恢复，表明VSMCs与内皮的逆行相互作用。这些结果表明，1-BP成为靶向血管TRPC 6通道的PAD治疗的潜在种子。
Retarded revascularization after progressive occlusion of large conductance arteries is a major cause of bad prognosis for peripheral artery disease (PAD). However, pharmacological treatment for PAD is still limited. We previously reported that suppression of transient receptor potential canonical (TRPC) 6 channel activity in vascular smooth muscle cells (VSMCs) facilitates VSMC differentiation without affecting proliferation and migration. In this study, we found that 1-benzilpiperadine derivative (1-BP), a selective inhibitor for TRPC3 and TRPC6 channel activities, induced VSMC differentiation. 1-BP-treated mice showed increased capillary arterialization and improvement of peripheral circulation and skeletal muscle mass after hind-limb ischemia (HLI) in mice. 1-BP had no additive effect on the facilitation of blood flow recovery after HLI in TRPC6-deficient mice, suggesting that suppression of TRPC6 underlies facilitation of the blood flow recovery by 1-BP. 1-BP also improved vascular nitric oxide bioavailability and blood flow recovery after HLI in hypercholesterolemic mice with endothelial dysfunction, suggesting the retrograde interaction from VSMCs to endothelium. These results suggest that 1-BP becomes a potential seed for PAD treatments that target vascular TRPC6 channels.
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