Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom.
The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom.
Am J Physiol Heart Circ Physiol. 2020 Dec 1;319(6):H1387-H1397. doi: 10.1152/ajpheart.00491.2020. Epub 2020 Oct 9.
Perivascular adipose tissue (PVAT) depots are metabolically active and play a major vasodilator role in healthy lean individuals. In obesity, they become inflamed and eosinophil-depleted and the anticontractile function is lost with the development of diabetes and hypertension. Moreover, eosinophil-deficient ΔdblGATA-1 mice lack PVAT anticontractile function and exhibit hypertension. Here, we have investigated the effects of inducing eosinophilia on PVAT function in health and obesity. Control, obese, and ΔdblGATA-1 mice were administered intraperitoneal injections of interleukin-33 (IL-33) for 5 days. Conscious restrained blood pressure was measured, and blood was collected for glucose and plasma measurements. Wire myography was used to assess the contractility of mesenteric resistance arteries. IL-33 injections induced a hypereosinophilic phenotype. Obese animals had significant elevations in blood pressure, blood glucose, and plasma insulin, which were normalized with IL-33. Blood glucose and insulin levels were also lowered in lean treated mice. In arteries from control mice, PVAT exerted an anticontractile effect on the vessels, which was enhanced with IL-33 treatment. In obese mice, loss of PVAT anticontractile function was rescued by IL-33. Exogenous application of IL-33 to isolated arteries induced a rapidly decaying endothelium-dependent vasodilation. The therapeutic effects were not seen in IL-33-treated ΔdblGATA-1 mice, thereby confirming that the eosinophil is crucial. In conclusion, IL-33 treatment restored PVAT anticontractile function in obesity and reversed development of hypertension, hyperglycemia, and hyperinsulinemia. These data suggest that targeting eosinophil numbers in PVAT offers a novel approach to the treatment of hypertension and type 2 diabetes in obesity. In this study, we have shown that administering IL-33 to obese mice will restore PVAT anticontractile function, and this is accompanied by normalized blood pressure, blood glucose, and plasma insulin. Moreover, the PVAT effect is enhanced in control mice given IL-33. IL-33 induced a hypereosinophilic phenotype in our mice, and the effects of IL-33 on PVAT function, blood pressure, and blood glucose are absent in eosinophil-deficient mice, suggesting that the effects of IL-33 are mediated via eosinophils.
血管周脂肪组织 (PVAT) 是代谢活跃的，在健康的瘦个体中发挥主要的血管舒张作用。在肥胖中，它们会发炎并耗尽嗜酸性粒细胞，并且随着糖尿病和高血压的发展，抗收缩功能丧失。此外，缺乏嗜酸性粒细胞的 ΔdblGATA-1 小鼠缺乏 PVAT 抗收缩功能并表现出高血压。在这里，我们研究了诱导嗜酸性粒细胞增多对健康和肥胖状态下 PVAT 功能的影响。给对照、肥胖和 ΔdblGATA-1 小鼠腹腔内注射白细胞介素 33 (IL-33) 5 天。测量清醒受限的血压，并采集血液进行血糖和血浆测量。线描肌动描记法用于评估肠系膜阻力动脉的收缩性。IL-33 注射诱导出嗜酸性粒细胞增多表型。肥胖动物的血压、血糖和血浆胰岛素显著升高，IL-33 治疗可使其正常化。瘦鼠经 IL-33 处理后血糖和胰岛素水平也降低。在对照小鼠的血管中，PVAT 对血管发挥抗收缩作用，IL-33 治疗可增强该作用。在肥胖小鼠中，IL-33 恢复了 PVAT 抗收缩功能的丧失。将外源性 IL-33 应用于分离的动脉中可诱导迅速衰减的内皮依赖性血管舒张。在接受 IL-33 治疗的 ΔdblGATA-1 小鼠中未观察到治疗效果，从而证实嗜酸性粒细胞是关键。总之，IL-33 治疗恢复了肥胖中的 PVAT 抗收缩功能，并逆转了高血压、高血糖和高胰岛素血症的发展。这些数据表明，靶向 PVAT 中的嗜酸性粒细胞数量为肥胖中的高血压和 2 型糖尿病的治疗提供了一种新方法。在这项研究中，我们表明给肥胖小鼠施用 IL-33 会恢复 PVAT 抗收缩功能，同时伴随血压、血糖和血浆胰岛素正常化。此外，给予 IL-33 的对照小鼠的 PVAT 作用增强。IL-33 在我们的小鼠中诱导出嗜酸性粒细胞增多表型，而缺乏嗜酸性粒细胞的 IL-33 对 PVAT 功能、血压和血糖的影响缺失，这表明 IL-33 的作用是通过嗜酸性粒细胞介导的。
