Nutrient-induced hyperosmosis evokes vasorelaxation via TRPV1 channel-mediated, endothelium-dependent, hyperpolarisation in healthy and colitis mice
Nutrient-induced hyperosmosis evokes vasorelaxation via TRPV1 channel-mediated, endothelium-dependent, hyperpolarisation in healthy and colitis mice
复制标题
营养诱导的高渗通过 TRPV1 通道介导的内皮依赖性超极化在健康小鼠和结肠炎小鼠中引起血管舒张
DOI：
10.1111/bph.15322
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发表时间：
2020-12-15
影响因子：
7.3
通讯作者：
Dong, Hui
中科院分区：
文献类型：
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作者：
Guo, Yanjun;Lu, Cheng;Dong, Hui
背景和目的在人类中，餐后肠系膜循环中的血流量显著增加，但营养物质引起的餐后肠系膜血管松弛的机制以及这一过程是否参与结肠炎的发病机制尚不清楚。在这里，我们研究了营养素对健康和结肠炎小鼠肠系膜动脉张力的直接作用及其潜在的分子机制。实验方法用葡聚糖硫酸钠诱导C57BL/6小鼠结肠炎。用线式肌图仪研究了营养诱导的人和小鼠肠系膜小动脉的血管松弛作用。应用选择性药物和阻断TRPV1通道的shRNA，对人血管内皮细胞和血管平滑肌细胞进行钙、钠离子成像。关键结果葡萄糖、钠和甘露醇通过高渗作用诱导人和小鼠肠系膜小动脉内皮依赖性的松弛。TRPV1、IKCa和SKCa通道的选择性阻断剂几乎可完全消除高渗诱导的血管松弛作用。葡萄糖显著刺激内皮细胞通过TRPV1通道的钙内流，这种作用可被选择性阻滞剂和阻断TRPV1通道的shRNA所减弱。辣椒素对葡萄糖诱导的血管松弛有协同作用。营养诱导的高渗还激活了Na+/K+-ATPase和Na/Ca交换器(NCX)，使VSMC[Ca~(2+)]~(2+)降低。结论：营养诱导的高渗通过TRPV1/Ca~(2+)/内皮依赖的超极化途径引起内皮依赖性的肠系膜血管松弛，从而增加正常的粘膜灌注量，这在我们的结肠炎模型中是受损的。TRPV1/Ca~(2+)/内皮依赖性超极化通路可能为慢性结肠炎、肠系膜缺血等低灌注性胃肠道疾病提供新的药物靶点。
Background and Purpose In humans, blood flow in the mesenteric circulation is greatly increased after meals, but the mechanisms underlying postprandial mesenteric vasorelaxation induced by nutrients and whether this process is involved in the pathogenesis of colitis, are not well understood. Here we have studied the direct actions of nutrients on mesenteric arterial tone and the underlying molecular mechanisms in healthy and colitis mice.Experimental Approach Colitis in C57BL/6 mice was induced with dextran sodium sulphate. Nutrient-induced vasorelaxation of mesenteric arterioles from humans and mice was studied with wire myograph assays. Ca2+ and Na+ imaging were performed in human vascular endothelial cells and vascular smooth muscle cells, using selective pharmacological agents and shRNA knockdown of TRPV1 channels.Key Results Glucose, sodium and mannitol concentration-dependently induced endothelium-dependent relaxation of human and mouse mesenteric arterioles via hyperosmotic action,. Hyperosmosis-induced vasorelaxation was almost abolished by selective blockers for TRPV1, IKCa and SKCa channels. Glucose markedly stimulated Ca2+ influx through endothelial TRPV1 channels, an effect attenuated by selective blockers and shRNA knockdown of TRPV1 channels. Capsaicin synergised the glucose-induced vasorelaxation. Nutrient-induced hyperosmosis also activated Na+/K+-ATPase and the Na/Ca exchanger (NCX) to decrease [Ca2+](i) in VSMCs. Glucose-induced vasorelaxation was impaired in mouse colitis.Conclusion and Implications Nutrient-induced hyperosmosis evoked endothelium-dependent mesenteric vasorelaxation via the TRPV1/Ca2+/ endothelium-dependent hyperpolarisation pathway to increase normal mucosal perfusion, which is impaired in our model of colitis. The TRPV1/Ca2+/ endothelium-dependent hyperpolarisation pathway could provide novel drug targets for gastrointestinal diseases with hypoperfusion, such as chronic colitis and mesenteric ischaemia.