The role of adipocyte eNOS in regulating vascular function

内皮型一氧化氮合酶(ENOS)是以首次发现的细胞类型命名的。使用全球eNOS缺陷小鼠的研究表明，eNOS具有降压、抗血栓和抗动脉粥样硬化的作用。到目前为止，eNOS的保护作用主要归因于内皮细胞产生的一氧化氮(NO)。然而，最近的研究表明，不仅血管内皮细胞，而且血管周围脂肪组织(PVAT)中的脂肪细胞也表达eNOS并参与血管NO的产生。然而，到目前为止，eNOS在脂肪细胞中的作用很少被研究，尤其是因为直到最近才有细胞特异性eNOS基因敲除小鼠。我们已经证明，只有当PVAT保持完整时，才能在饮食诱导的肥胖小鼠的主动脉中检测到NO介导的血管扩张减少(从而导致血管功能障碍)。此外，这些肥胖小鼠的PVAT-eNOS，而不是内皮-eNOS被发现处于功能障碍状态。这些数据表明，在一定的病理条件下，PVAT-eNOS在血管功能障碍中可能比eNOS在血管内皮细胞中的表达更重要。在本项目中，将建立细胞特异性eNOS基因敲除小鼠，以研究脂肪细胞eNOS和内皮eNOS在调节血管功能和血压中的相对作用和贡献。这些研究将在生理条件下、病理条件下(例如，在诱导饮食诱导的肥胖之后)以及在应用eNOS靶向药物治疗之后进行。此外，还将鉴定脂肪细胞和内皮细胞中的NO调节基因，并分析肥胖相关的eNOS功能障碍在PVAT中的分子机制。动物实验的结果将在体外的人体血管上得到验证。

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.