Servicenavigation

Project Details

Back

Projekt Print View

The role of adipocyte eNOS in regulating vascular function

Subject Area Cardiology, Angiology
Pharmacology
Term from 2018 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 407937360
 
Final Report Year 2024

Final Report Abstract

To study the role of endothelial nitric oxide synthase (eNOS) in adipocytes, we generated an adipocyte-specific eNOS-knockout mouse line (A-Nos3-KO). eNOS was selectively deleted in adipocytes, but not in the aorta, liver or brain. Under physiological conditions (feeding with normal chow), the lack of eNOS in the perivascular adipose tissue (PVAT) led to a reduction in the vasodilating effect of PVAT, confirming the concept that NO is a PVAT-derived relaxation factor. The vasodilator response to acetylcholine was reduced in the PVAT-containing aorta and mesenteric artery (MA) of A-Nos3-KO mice compared to control mice. Interestingly, the vasodilation function of A-Nos3-KO mice was also reduced in PVAT-free aorta and MA in ex vivo experiments, attributable to enhanced remodeling of the vascular wall. Under the condition of high-fat diet (HFD)-induced obesity, the vasodilator function of the PVAT got completely lost in the A-Nos3- KO mice, associated with PVAT inflammation, oxidative stress, and enhanced chemerin expression in the PVAT. The loss of adipocyte eNOS in obese mice resulted in exacerbation of vascular remodeling and potentiation of HFD-induced hypertension. In ex vivo experiments, the upregulation of remodeling genes induced by serum from HFD-treated A-Nos3-KO mice was preventable by a neutralizing antibody against chemerin, indicating a key role of the adipokine. Unexpectedly, HFD-treated A-Nos3-KO mice showed an improved liver phenotype, including normalized liver weight, attenuated liver inflammation, reduced hepatic steatosis and fibrogenesis. Oxidative stress and inflammation were reduced in visceral adipose tissues of HFD-fed A-Nos3-KO mice compared to HFD- treated control mice. Also the serum levels of monocyte chemoattractant protein 1 (MCP1), tissue inhibitor 1 of metalloproteinases (TIMP1), and plasminogen activator inhibitor 1 (PAI1) were decreased, whereas growth differentiation factor 15 (GDF15) was increased in the serum. It is conceivable that the improved liver pathology was due to the regulation of systemic levels of MCP1, TIMP1, PAI and GDF15. These results indicate that eNOS in different adipose tissues may have different roles. The PVAT-eNOS protects against obesity-associated hypertension by inducing vasodilation, preventing vascular remodeling, and limiting chemerin expression. However, the eNOS enzyme in the visceral adipose tissue facilitates the production of factors that directly or indirectly promote the development of metabolic dysfunction-associated steatotic liver disease and steatohepatitis.

Publications

 
 

Additional Information

© 2026 DFG Disclaimer / Copyright / Privacy Policy

Textvergrößerung und Kontrastanpassung