血管内皮生长因子诱导性骨桥蛋白表达可通过外膜纤维母细胞中的Flt-1介导血管炎症和新生内膜形成

Gao, P.-J.; Department of Hypertension, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Rd, Shanghai 200025, China; email:gaopingjin@yahoo.com.cn

Objective-Adventitia acts as an active participant in vascular inflammation but the precise mechanism underlying adventitia-mediated vascular inflammation is not fully understood. In this study, we sought to determine whether vascular endothelial growth factor (VEGF) regulates osteopontin (OPN) expression through Flt-1 in adventitial fibroblasts (AFs) to mediate vascular inflammation and neointima formation. Methods and Results-In primary cultured AFs, VEGF increased intracellular and secreted OPN expression in a time-and dose-dependent manner, which was effectively suppressed by a specific anti-Flt-1 hexapeptide. Interestingly, VEGF treatment of AFs enhanced the capability of AF-conditioned medium to stimulate macrophages chemotaxis, and this effect was attenuated after blockade of OPN from AF-conditioned medium. Furthermore, perivascular delivery of anti-Flt-1 peptide preferentially concentrated in the adventitia resulted in a decrease of neointima formation after balloon injury in carotid arteries. The inhibition of neointima formation was preceded by significant reduction of VEGF and OPN expression with concurrent macrophage infiltration into adventitia after injury. Activation of extracellular signal-regulated kinase 1/2 pathway was involved in OPN upregulation and macrophage chemotaxis. Conclusion-These results demonstrate that VEGF/Flt-1 signaling plays a significant role in vascular inflammation and neointima formation by regulating OPN expression in AFs and provide insight into Flt-1 as a potential therapeutic target for vascular diseases. © 2012 American Heart Association, Inc.

Laboratory of Vascular Biology and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China