Vascular Endothelial Growth Factor-Induced Osteopontin Expression Mediates Vascular Inflammation and Neointima Formation via Flt-1 in Adventitial Fibroblasts
Vascular Endothelial Growth Factor-Induced Osteopontin Expression Mediates Vascular Inflammation and Neointima Formation via Flt-1 in Adventitial Fibroblasts
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DOI：
10.1161/atvbaha.112.255216
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发表时间：
2012-09-01
影响因子：
8.7
通讯作者：
Gao, Ping-Jin
中科院分区：
文献类型：
--
作者：
Li, Xiao-Dong;Chen, Jing;Gao, Ping-Jin
外膜作为血管炎症的积极参与者，但外膜介导的血管炎症的确切机制尚未完全了解。在这项研究中，我们试图确定是否血管内皮生长因子（VEGF）调节骨桥蛋白（OPN）的表达，通过Flt-1在外膜成纤维细胞（AFs）介导血管炎症和neointimaformation.Methods和Results-In原代培养的AFs，VEGF增加细胞内和分泌的OPN表达的时间和剂量依赖性的方式，这是有效地抑制了特定的抗Flt-1六肽。有趣的是，VEGF处理AF增强了AF条件培养基刺激巨噬细胞趋化性的能力，并且这种作用在AF条件培养基中的OPN阻断后减弱。此外，血管周围递送的抗Flt-1肽优先集中在外膜导致减少颈动脉球囊损伤后的新生内膜形成。在抑制新生内膜形成之前，VEGF和OPN表达显著减少，同时损伤后巨噬细胞浸润到外膜中。细胞外信号调节激酶1/2通路的激活参与OPN上调和巨噬细胞chemotaxis.Conclusion-These结果表明，VEGF/Flt-1信号在血管炎症和新生内膜形成中起着重要的作用，通过调节OPN在AF的表达，并提供洞察Flt-1作为血管疾病的潜在治疗靶点。（Arterioscler Thromb Vasc Biol.2012;32：2250-2258.）
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. (Arterioscler Thromb Vasc Biol. 2012;32:2250-2258.)