Perivascular adipose tissue-derived nitric oxide compensates endothelial dysfunction in aged pre-atherosclerotic apolipoprotein E-deficient rats

• Published in: Vascular pharmacology Vol. 142; p. 106945
• Main Authors: Nakladal, D., Sijbesma, J.W.A., Visser, L.M., Tietge, U.J.F., Slart, R.H.J.A., Deelman, L.E., Henning, R.H., Hillebrands, J.L., Buikema, H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2022; Elsevier Science Ltd
• Subjects: Adiponectin; Adipose tissue; Adipose Tissue - metabolism; Animals; Aorta; Apolipoprotein E; Apolipoproteins; Apolipoproteins E - genetics; Arteriosclerosis; Atherosclerosis; Atherosclerosis - metabolism; Body fat; Cholesterol; Cholinergics; Diet; Endothelium; Gene expression; High fat diet; Hyperlipidemia; IL-1β; Inflammation; Interleukin 6; Macrophages; Medicin och hälsovetenskap; Monocyte chemoattractant protein 1; Nitric oxide; Nitric Oxide - metabolism; Nitric-oxide synthase; Perivascular adipose tissue; Positron Emission Tomography Computed Tomography; Rats; Rats, Sprague-Dawley; Thickness ratio; Triglycerides; Vascular relaxation; [18F]FDG; Perivascular adipose tissue; WAT; Vascular relaxation; CT; EDR; Apolipoprotein E; BAT; PE; KCl; LDL; FFPE; Nitric oxide; VLDL; Atherosclerosis; ApoE; L-NMMA; PVAT; LDLr; EDHF; Emax; CHD; PET
• ISSN: 1537-1891; 1879-3649; 1879-3649
• DOI: 10.1016/j.vph.2021.106945

Atherosclerosis is a major contributor to global mortality and is accompanied by vascular inflammation and endothelial dysfunction. Perivascular adipose tissue (PVAT) is an established regulator of vascular function with emerging implications in atherosclerosis. We investigated the modulation of aortic relaxation by PVAT in aged rats with apolipoprotein E deficiency (ApoE−/−) fed a high-fat diet as a model of early atherosclerosis. ApoE−/− rats (N = 7) and wild-type Sprague-Dawley controls (ApoE+/+, N = 8) received high-fat diet for 51 weeks. Hyperlipidemia was confirmed in ApoE−/− rats by elevated plasma cholesterol (p < 0.001) and triglyceride (p = 0.025) levels. Early atherosclerosis was supported by increased intima/media thickness ratio (p < 0.01) and ED1-positive macrophage influx in ApoE−/− aortic intima (p < 0.001). Inflammation in ApoE−/− PVAT was characteristic by an increased [18F]FDG uptake (p < 0.01), ED1-positive macrophage influx (p = 0.0003), mRNA expression levels of CD68 (p < 0.001) and IL-1β (p < 0.01), and upregulated iNOS protein (p = 0.011). The mRNAs of MCP-1, IL-6 and adiponectin remained unchanged in PVAT. Aortic PVAT volume measured with micro-PET/CT was increased in ApoE−/− rats (p < 0.01). Maximal endothelium-dependent relaxation (EDR) to acetylcholine in ApoE−/− aortic rings without PVAT was severely impaired (p = 0.012) compared with controls, while ApoE−/− aortic rings with PVAT showed higher EDR than controls. All EDR responses were blocked by L-NMMA and the expression of eNOS mRNA was increased in ApoE−/− PVAT (p = 0.035). Using a rat ApoE−/− model of early atherosclerosis, we capture a novel mechanism by which inflammatory PVAT compensates severe endothelial dysfunction by contributing NO upon cholinergic stimulation. [Display omitted]