Vascular Endothelial Growth Factor Is Necessary in the Development of Arteriosclerosis by Recruiting/Activating Monocytes in a Rat Model of Long-Term Inhibition of Nitric Oxide Synthesis
Vascular Endothelial Growth Factor Is Necessary in the Development of Arteriosclerosis by Recruiting/Activating Monocytes in a Rat Model of Long-Term Inhibition of Nitric Oxide Synthesis
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DOI：
10.1161/hc0902.104718
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发表时间：
2002-03
期刊：
影响因子：
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通讯作者：
Qingwei Zhao;K. Egashira;S. Inoue;M. Usui;S. Kitamoto;W. Ni;M. Ishibashi;K. Hiasa;T. Ichiki;M. Shibuya;A. Takeshita
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文献类型：
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作者：
Qingwei Zhao;K. Egashira;S. Inoue;M. Usui;S. Kitamoto;W. Ni;M. Ishibashi;K. Hiasa;T. Ichiki;M. Shibuya;A. Takeshita
背景-目前尚不清楚血管内皮生长因子(VEGF)是促动脉硬化因子还是抗动脉硬化因子。我们最近报道，长期应用N-硝基-L-精氨酸甲酯(L-NAME)抑制一氧化氮可诱导冠状动脉血管炎症和动脉硬化。方法和结果--我们使用这个动物模型来研究血管内皮生长因子在动脉硬化中的作用。我们通过将编码小鼠可溶性Flt-1(sFlt-1)基因的DNA导入大腿肌肉，在体内阻断了血管内皮生长因子的活性。可溶性Flt-1可以通过隔离血管内皮生长因子和作为显性负抑制血管内皮生长因子受体的作用来抑制血管内皮细胞生长因子的活性。在给予血管紧张素转换酶抑制剂、血管紧张素II受体拮抗剂或中和单核细胞趋化蛋白-1抗体的情况下，我们观察到在给药后3d内血管炎症与血管内皮生长因子表达增加相关。SFlt-1基因转移减轻早期血管炎症，预防晚期动脉硬化。SFlt-1基因转移还抑制了单核细胞趋化蛋白-1和转化生长因子-1的表达增加，表明形成了一个正反馈环路，导致动脉硬化。结论：在该模型中，通过调节单核细胞的募集和激活，血管内皮生长因子在动脉硬化的发展中是必需的。
Background—It remains unclear whether vascular endothelial growth factor (VEGF) is a proarteriosclerotic or an antiarteriosclerotic factor. We recently reported that long-term inhibition of nitric oxide by administering N-nitro-l-arginine methyl ester (L-NAME) induces coronary vascular inflammation and arteriosclerosis. Methods and Results—We used this animal model to investigate the role of VEGF in arteriosclerosis. We blocked VEGF activity in vivo by transfecting with plasmid DNA encoding the murine soluble FLT-1 (sFLT-1) gene into thigh muscle. Soluble FLT-1 can suppress VEGF activity both by sequestering VEGF and by functioning as a dominant-negative inhibitor of VEGF receptors. We observed vascular inflammation associated with increased VEGF expression within 3 days of L-NAME administration, which was prevented by pretreatment with ACE inhibitor, angiotensin II receptor antagonist, or neutralizing monocyte chemoattractant protein-1 antibody. The sFLT-1 gene transfer attenuated the early vascular inflammation and prevented late arteriosclerosis. The sFLT-1 gene transfer also inhibited increased expression of monocyte chemoattractant protein-1 and transforming growth factor-, indicating creation of a positive feedback loop to cause arteriosclerosis. Conclusions—VEGF is necessary in the development of arteriosclerosis by mediating monocyte recruitment and activation in this model.