Supplemental Digital Content is available in the text. Obesity-related hypertension is one of the world’s leading causes of death and yet little is understood as to how it develops. As a result, effective targeted therapies are lacking and pharmacological treatment is unfocused. To investigate underlying microvascular mechanisms, we studied small artery dysfunction in a high fat–fed mouse model of obesity. Pressure-induced constriction and responses to endothelial and vascular smooth muscle agonists were studied using myography; the corresponding intracellular Ca2+ signaling pathways were examined using confocal microscopy. Principally, we observed that the enhanced basal tone of mesenteric resistance arteries was due to failure of intraluminal pressure-induced Ca2+ spark activation of the large conductance Ca2+ activated K+ potassium channel (BK) within vascular smooth muscle cells. Specifically, the uncoupling site of this mechanotransduction pathway was at the sarcoplasmic reticulum, distal to intraluminal pressure-induced oxidation of Protein Kinase G. In contrast, the vasodilatory function of the endothelium and the underlying endothelial IP-3 and TRPV4 (vanilloid 4 transient receptor potential ion channel) Ca2+ signaling pathways were not affected by the high-fat diet or the elevated blood pressure. There were no structural alterations of the arterial wall. Our work emphasizes the importance of the intricate cellular pathway by which intraluminal pressure maintains Ca2+ spark vasoregulation in the origin of obesity-related hypertension and suggests previously unsuspected avenues for pharmacological intervention.

中文翻译：

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压力诱导的 Ca 2+ 火花对阻力动脉的血管调节的破坏，而不是内皮功能障碍，是肥胖相关高血压的基础

补充数字内容在文本中可用。肥胖相关的高血压是世界上主要的死亡原因之一，但对其如何发展却知之甚少。因此，缺乏有效的靶向治疗，药物治疗没有重点。为了研究潜在的微血管机制，我们在高脂喂养的肥胖小鼠模型中研究了小动脉功能障碍。使用肌电图研究压力引起的收缩和对内皮和血管平滑肌激动剂的反应；使用共聚焦显微镜检查相应的细胞内 Ca2+ 信号通路。原则上，我们观察到肠系膜阻力动脉的基底张力增强是由于血管平滑肌细胞内的大电导 Ca2+ 激活的 K+ 钾通道 (BK) 的管腔内压力诱导的 Ca2+ 火花激活失败。具体来说，这种机械转导途径的解偶联位点位于肌浆网，在腔内压力诱导的蛋白激酶 G 氧化的远端。相反，内皮的血管舒张功能和潜在的内皮 IP-3 和 TRPV4（香草素 4 瞬时受体潜在离子通道）Ca2+ 信号通路不受高脂饮食或血压升高的影响。动脉壁没有结构改变。