The role of adipocyte eNOS in regulating vascular function

脂肪细胞eNOS在调节血管功能中的作用

• 批准号: 407937360
• 负责人: Professor Dr. Huige Li
• 金额: --
• 依托单位: Institut für Pharmakologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/407937360?language=en
• 关键词: role; adipocyte; eNOS; regulating; vascular

The enzyme endothelial nitric oxide synthase (eNOS) is named after the cell type in which it was first discovered. Studies using global eNOS-deficient mice have shown that eNOS possesses antihypertensive, antithrombotic and anti-atherosclerotic effects. To date, the protective effects of eNOS have been mainly attributed to nitric oxide (NO) derived from the endothelium. However, recent studies have demonstrated that not only endothelial cells, but also adipocytes in the perivascular adipose tissue (PVAT) express eNOS and contribute to the production of vascular NO. However, the role of eNOS in adipocytes has been rarely investigated so far, among others because cell-specific eNOS knockout mice were not available until recently. We have shown that a reduction in NO-mediated vasodilatation (and thus a vascular dysfunction) was only detectable in the aorta of diet-induced obese mice when the PVAT remained intact. Moreover, PVAT-eNOS, but not Endothelial-eNOS of these obese mice was found to be in a dysfunctional state. These data indicate that, under certain pathological conditions, PVAT-eNOS may play a more important role for the vascular dysfunction than eNOS expressed in endothelial cells. In this project, cell-specific eNOS knockout mice will be generated in order to investigate the relative role and contribution of adipocyte eNOS and endothelial eNOS for the regulation of vascular function and blood pressure. The studies will be performed under physiological conditions, under pathological conditions (e.g. after induction of a diet-induced obesity) as well as after the application of eNOS-targeting pharmacological therapies. Furthermore, NO-regulated genes in adipocytes and endothelial cells will be identified and the molecular mechanisms of obesity-related eNOS dysfunction in the PVAT will be analyzed. The results obtained in the animal experiments will be verified on human blood vessels ex vivo.

内皮型一氧化氮合酶（eNOS）是以其首次发现的细胞类型命名的。使用整体eNOS缺陷小鼠的研究表明，eNOS具有抗高血压、抗血栓形成和抗动脉粥样硬化作用。迄今为止，eNOS的保护作用主要归因于来自内皮的一氧化氮（NO）。然而，最近的研究表明，不仅内皮细胞，而且在血管周围脂肪组织（PVAT）的脂肪细胞表达eNOS，并有助于血管NO的产生。然而，eNOS在脂肪细胞中的作用很少调查到目前为止，其中包括因为细胞特异性eNOS敲除小鼠直到最近才可用。我们已经证明，只有当PVAT保持完整时，在饮食诱导的肥胖小鼠的主动脉中才能检测到NO介导的血管舒张（从而导致血管功能障碍）的减少。此外，发现这些肥胖小鼠的PVAT-eNOS而不是内皮-eNOS处于功能障碍状态。这些数据表明，在一定的病理条件下，PVAT-eNOS可能发挥更重要的作用，血管功能障碍比eNOS表达的内皮细胞。在本项目中，将产生细胞特异性eNOS敲除小鼠，以研究脂肪细胞eNOS和内皮细胞eNOS对血管功能和血压调节的相对作用和贡献。这些研究将在生理条件下、病理条件下（例如，诱导饮食诱导的肥胖症后）以及应用eNOS靶向药物治疗后进行。此外，将确定脂肪细胞和内皮细胞中的NO调节基因，并分析PVAT中肥胖相关的eNOS功能障碍的分子机制。将在离体人体血管上验证动物实验中获得的结果。