The role of adipocyte eNOS in regulating vascular function

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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.