Induction of vascular endothelial growth factor in balloon-injured baboon arteries - A novel role for reactive oxygen species in atherosclerosis
Induction of vascular endothelial growth factor in balloon-injured baboon arteries - A novel role for reactive oxygen species in atherosclerosis
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DOI：
10.1161/01.res.81.1.24
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发表时间：
1997-07-01
影响因子：
20.1
通讯作者：
Patterson, C
中科院分区：
文献类型：
--
作者：
Ruef, J;Hu, ZY;Patterson, C
新生血管是动脉粥样硬化斑块和再狭窄病变中新内膜形成的标志。血管内皮生长因子（VEGF）促进新生血管的生长，而氧化应激是血管细胞增殖的一个有效因素。为了研究新生血管形成的机制，我们用H2O2处理人和大鼠血管平滑肌细胞（VSMCs）。Northern blot分析显示VEGF mRNA呈剂量和时间依赖性增加，在3小时（200 mu mol/L）时最大增加4倍。通过免疫印迹和酶联免疫吸附法检测，VEGF蛋白表达和分泌相似地增加。用200 μ mol/L H2O2培养的VSMCs条件培养基处理人脐静脉内皮细胞。胸腺嘧啶掺入测量的DNA合成比对照组增加了4倍，这一效应被中和性抗vegf抗体阻断。脂质过氧化产物4-羟基壬烯醛（1 μ mol/L）是人类动脉粥样硬化病变中存在的一种内源性活性氧，也以类似的时间依赖性方式增加VSMCs中VEGF的分泌。免疫组织化学染色和原位杂交显示，与对照切片相比，新生内膜和中间膜的分离区域VEGF表达增加，且表达与4-羟基壬烯醛的产生相关。VEGF表达的调节因子，如活性氧，可能会促进动脉粥样硬化和再狭窄动脉的新生血管。
Neovascularization is a hallmark of neointimal formation in atherosclerotic plaques and restenotic lesions. Vascular endothelial growth factor (VEGF) promotes neovascular growth, whereas oxidative stress is a potent factor in vascular cell proliferation. To investigate the mechanisms of neovascular formation, we treated human and rat vascular smooth muscle cells (VSMCs) with H2O2. Northern blot analysis demonstrated a dose- and time-dependent increase in VEGF mRNA, with a maximum of 4-fold at 3 hours (200 mu mol/L). As determined by immunoblotting and enzyme-linked immunosorbent assay, VEGF protein expression and secretion were similarly increased. Human umbilical vein endothelial cells were treated with conditioned medium from VSMCs incubated with 200 mu mol/L H2O2. DNA synthesis, measured by thymidine incorporation, was increased 4-fold compared with control, an effect that was blocked by a neutralizing anti-VEGF antibody. The lipid peroxidation product 4-hydroxynonenal (1 mu mol/L), an endogenous reactive oxygen species present in human atherosclerotic lesions, also increased VEGF secretion in VSMCs in a similar time-dependent fashion. Immunohistochemical staining and in situ hybridization of aortic sections from balloon-injured baboons demonstrated increased VEGF expression in discrete areas of the neointima and media compared with control sections, and expression correlated with the generation of 4-hydroxynonenal. Regulators of VEGF expression, such as reactive oxygen species, may enhance neovascularization of atherosclerotic and restenotic arteries.