Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands.
Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands.
Vascul Pharmacol. 2022 Feb;142:106945. doi: 10.1016/j.vph.2021.106945. Epub 2021 Nov 18.
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.
动脉粥样硬化是全球死亡率的主要原因，其伴随血管炎症和内皮功能障碍。血管周围脂肪组织（PVAT）是血管功能的既定调节剂，在动脉粥样硬化中具有新的意义。我们研究了载脂蛋白 E 缺乏（ApoE）大鼠主动脉松弛受 PVAT 调节的情况，这些大鼠喂食高脂肪饮食，作为早期动脉粥样硬化的模型。
ApoE 大鼠（N=7）和野生型 Sprague-Dawley 对照（ApoE，N=8）接受高脂肪饮食 51 周。ApoE 大鼠的高脂血症通过升高的血浆胆固醇（p<0.001）和甘油三酯（p=0.025）水平得到确认。早期动脉粥样硬化得到证实，ApoE 主动脉内膜中内膜/中膜厚度比增加（p<0.01）和 ED1 阳性巨噬细胞流入增加（p<0.001）。ApoE 脂肪组织中的炎症表现为 [18F]FDG 摄取增加（p<0.01）、ED1 阳性巨噬细胞流入增加（p=0.0003）、CD68mRNA 表达水平升高（p<0.001）和 IL-1β（p<0.01）以及 iNOS 蛋白上调（p=0.011）。PVAT 中的 MCP-1、IL-6 和脂联素 mRNA 保持不变。ApoE 大鼠的主动脉 PVAT 体积通过 micro-PET/CT 测量增加（p<0.01）。与对照组相比，没有 PVAT 的 ApoE 主动脉环对乙酰胆碱的最大内皮依赖性松弛（EDR）严重受损（p=0.012），而有 PVAT 的 ApoE 主动脉环的 EDR 高于对照组。所有 EDR 反应均被 L-NMMA 阻断，ApoE PVAT 中的 eNOS mRNA 表达增加（p=0.035）。
使用载脂蛋白 E 大鼠的早期动脉粥样硬化模型，我们捕捉到一种新的机制，即炎症性 PVAT 通过在胆碱能刺激时产生 NO 来补偿严重的内皮功能障碍。
