Vascular endothelial growth factor-A induces plaque expansion in ApoE knock-out mice by promoting de novo leukocyte recruitment
Vascular endothelial growth factor-A induces plaque expansion in ApoE knock-out mice by promoting de novo leukocyte recruitment
复制标题
DOI：
10.1182/blood-2006-07-031773
复制
发表时间：
2007-01-01
期刊：
影响因子：
20.3
通讯作者：
Biessen, Eric A. L.
中科院分区：
文献类型：
--
作者：
Lucerna, Markus;Zernecke, Alma;Biessen, Eric A. L.
血管内皮生长因子-A在临床试验中广泛用于治疗心肌缺血。最近提出VEGF-A以促炎方式起作用，这可能在基于VEGF-A的治疗中加重邻近动脉粥样硬化的形成。为了评估潜在的旁观者效应，在ApoE（-/-）小鼠的晚期动脉粥样硬化斑块中局灶性过表达VEGF-A。剪切诱导的颈动脉斑块与Ad.hVEGF-A经腔孵育，导致VEGF-A的新生内膜过表达。预先存在的病变的Ad.hVEGF-A治疗被认为促进斑块扩张，伴随着巨噬细胞和脂质含量的增加，而它降低了胶原蛋白含量。一般来说，Ad.hVEGF-A处理的斑块显示出更脆弱的表型。VEGF-A过度表达并不伴随着新生内膜微血管发育的增加，这表明VEGF-A通过一种不依赖于血管生成的机制使动脉粥样硬化斑块不稳定。活体显微镜证实，用Ad.hVEGF-A处理导致单核细胞粘附增加，这是由VCAM-1/PECAM-1依赖性途径介导的。VEGF-A确实诱导内皮细胞中VCAM-1和PECAM-1的差异表达。我们的数据强调了定期监测VEGF-A应用部位附近狭窄血管的重要性。我们认为，VCAM 1/PECAM-1导向的联合治疗可能是预防心血管疾病患者局灶性VEGF-A治疗的旁观者效应的有效策略。
Vascular endothelial growth factor-A is widely used in clinical trials for the treatment of cardiac ischemia. VEGF-A was recently suggested to act in a proinflammatory manner, which could aggravate adjacent atherogenesis in VEGF-A-based therapy. To assess potential bystander effects, VEGF-A was focally overexpressed in advanced atherosclerotic plaques in ApoE(-/-) mice. Sheer-induced carotid artery plaques were transluminally incubated with Ad.hVEGF-A leading to neointimal overexpression of VEGF-A. Ad.hVEGF-A treatment of pre-existing lesions was seen to promote plaque expansion, with a concomitant increase in macrophage and lipid content, whereas it lowered collagen content. In general, Ad.hVEGF-A-treated plaques displayed a more vulnerable phenotype. VEGF-A overexpression was not accompanied by increased microvessel development in the neointima, suggesting that VEGF-A destabilizes atherosclerotic plaques through an angiogenesis-independent mechanism. Intravital microscopy confirmed that treatment with Ad.hVEGF-A led to an increased monocyte adhesion, which was mediated by a VCAM-1/PECAM-1-dependent pathway. VEGF-A indeed induced a differential expression of VCAM-1 and PECAM-1 in endothelial cells. Our data underline the importance of regular monitoring of stenotic vessels adjacent to the site of VEGF-A application. We propose that VCAM1/PECAM-1 -directed cotherapy may be an efficient strategy to prevent bystander effects of focal VEGF-A therapy in patients suffering from cardiovascular disease.