Department of Cardiology and Pulmonary Medicine, University Medical Center Goettingen, Georg August University of Goettingen, Goettingen, Germany.
Arterioscler Thromb Vasc Biol. 2013 May;33(5):980-7. doi: 10.1161/ATVBAHA.113.301393. Epub 2013 Mar 21.
Clinical and experimental evidence suggests that periadventitial adipose tissue may modulate vascular lesion formation. The aim of this study was to determine the role of perivascular leptin expression on neointima formation and to differentiate it from local inflammation and systemically elevated leptin levels.
Increased neointima formation after carotid artery injury was observed in hyperleptinemic, diet-induced obese wild-type mice, but not in leptin-deficient ob/ob mice. High-fat diet was associated with increased leptin expression in visceral adipose tissue (VAT) as well as in perivascular adipose tissue. Perivascular leptin overexpression achieved by adenoviral vectors enhanced intimal cell proliferation and neointima formation in wild-type mice, but not in leptin receptor-deficient mice. Perivascular transplantation of VAT from high-fat diet-induced obese wild-type mice around the carotid artery of immunodeficient mice also promoted neointima formation, without affecting body weight or systemic leptin levels, and this effect was absent, if VAT from ob/ob mice was used. On the contrary, perivascular transplantation of VAT from ob/ob mice fed high-fat diet, characterized by marked immune cell accumulation, promoted neointimal hyperplasia also in the absence of leptin. In vitro, recombinant leptin and VAT-conditioned medium increased human arterial smooth muscle cell proliferation in a (partly) leptin-dependent manner.
Our findings suggest that locally elevated leptin levels may promote neointima formation, independent of obesity and systemic hyperleptinemia, but also underline the importance of perivascular inflammation in mediating the increased cardiovascular risk in obesity.
临床和实验证据表明，血管外膜脂肪组织可能调节血管损伤形成。本研究旨在确定血管周瘦素表达在新生内膜形成中的作用，并将其与局部炎症和全身性瘦素水平升高区分开来。
在高脂饮食诱导的肥胖野生型小鼠中观察到颈动脉损伤后新生内膜形成增加，但在瘦素缺乏型 ob/ob 小鼠中则没有。高脂饮食与内脏脂肪组织（VAT）和血管周脂肪组织中瘦素表达增加有关。通过腺病毒载体实现的血管周瘦素过表达增强了野生型小鼠的内膜细胞增殖和新生内膜形成，但在瘦素受体缺陷型小鼠中则没有。将高脂饮食诱导肥胖的野生型小鼠的 VAT 通过血管周移植到免疫缺陷小鼠的颈动脉周围，也促进了新生内膜形成，而不影响体重或全身瘦素水平，如果使用 ob/ob 小鼠的 VAT，则没有这种作用。相反，如果 VAT 来源于高脂饮食喂养的 ob/ob 小鼠，其特征是明显的免疫细胞积聚，也会促进新生内膜增生，而与瘦素无关。在体外，重组瘦素和 VAT 条件培养基以（部分）依赖瘦素的方式增加人动脉平滑肌细胞的增殖。
我们的研究结果表明，局部升高的瘦素水平可能促进新生内膜形成，独立于肥胖和全身性高瘦素血症，但也强调了血管周炎症在介导肥胖患者心血管风险增加方面的重要性。
