Division of Translational Research, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
PLoS One. 2011;6(12):e29351. doi: 10.1371/journal.pone.0029351. Epub 2011 Dec 20.
The mechanisms that lead from obesity to atherosclerotic disease are not fully understood. Obesity involves angiogenesis in which vascular endothelial growth factor-A (VEGF-A) plays a key role. On the other hand, vascular endothelial growth factor-C (VEGF-C) plays a pivotal role in lymphangiogenesis. Circulating levels of VEGF-A and VEGF-C are elevated in sera from obese subjects. However, relationships of VEGF-C with atherosclerotic risk factors and atherosclerosis are unknown. We determined circulating levels of VEGF-A and VEGF-C in 423 consecutive subjects not receiving any drugs at the Health Evaluation Center. After adjusting for age and gender, VEGF-A levels were significantly and more strongly correlated with the body mass index (BMI) and waist circumference than VEGF-C. Conversely, VEGF-C levels were significantly and more closely correlated with metabolic (e.g., fasting plasma glucose, hemoglobin A1c, immunoreactive insulin, and the homeostasis model assessment of insulin resistance) and lipid parameters (e.g., triglycerides, total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), and non-high-density-lipoprotein cholesterol (non-HDL-C)) than VEGF-A. Stepwise regression analyses revealed that independent determinants of VEGF-A were the BMI and age, whereas strong independent determinants of VEGF-C were age, triglycerides, and non-HDL-C. In apolipoprotein E-deficient mice fed a high-fat-diet (HFD) or normal chow (NC) for 16 weeks, levels of VEGF-A were not significantly different between the two groups. However, levels of VEGF-C were significantly higher in HFD mice with advanced atherosclerosis and marked hypercholesterolemia than NC mice. Furthermore, immunohistochemistry revealed that the expression of VEGF-C in atheromatous plaque of the aortic sinus was significantly intensified by feeding HFD compared to NC, while that of VEGF-A was not. In conclusion, these findings demonstrate that VEGF-C, rather than VEGF-A, is closely related to dyslipidemia and atherosclerosis.
导致肥胖与动脉粥样硬化疾病的机制尚未完全阐明。肥胖涉及血管生成，其中血管内皮生长因子-A（VEGF-A）起着关键作用。另一方面，血管内皮生长因子-C（VEGF-C）在淋巴管生成中起着关键作用。肥胖患者血清中 VEGF-A 和 VEGF-C 的循环水平升高。然而，VEGF-C 与动脉粥样硬化危险因素和动脉粥样硬化的关系尚不清楚。我们在健康评估中心连续测定了 423 例未服用任何药物的受试者的循环 VEGF-A 和 VEGF-C 水平。在调整年龄和性别后，VEGF-A 水平与体重指数（BMI）和腰围的相关性显著且更强，而 VEGF-C 则相反。相反，VEGF-C 水平与代谢（例如空腹血糖、糖化血红蛋白 A1c、免疫反应性胰岛素和胰岛素抵抗的稳态模型评估）和脂质参数（例如甘油三酯、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）和非高密度脂蛋白胆固醇（非-HDL-C））的相关性更显著。逐步回归分析显示，VEGF-A 的独立决定因素是 BMI 和年龄，而 VEGF-C 的独立决定因素是年龄、甘油三酯和非-HDL-C。在高脂饮食（HFD）或正常饮食（NC）喂养 16 周的载脂蛋白 E 缺陷小鼠中，两组之间 VEGF-A 的水平没有显著差异。然而，在动脉粥样硬化严重且胆固醇显著升高的 HFD 小鼠中，VEGF-C 的水平明显高于 NC 小鼠。此外，免疫组织化学显示，与 NC 相比，HFD 喂养显著增强了主动脉窦粥样斑块中 VEGF-C 的表达，而 VEGF-A 的表达则没有。总之，这些发现表明，VEGF-C 与血脂异常和动脉粥样硬化密切相关，而不是 VEGF-A。
