ATV：高平进等血管外膜介导炎症反应的研究获进展

近日，国际学术期刊《Arteriosclerosis, Thrombosis, and Vascular Biology》在线发表了中国科学院上海生命科学研究院/上海交通大学医学院健康科学研究所和瑞金医院上海市高血压研究所高平进课题组最新研究成果：“VEGF-induced Osteopontin Expression Mediates Vascular Inflammation and Neointima Formation via Flt-1 in Adventitial Fibroblasts”。

血管炎症是血管损伤过程中重要的始发因素能够导致不同的心血管疾病。传统观念认为血管外膜对整个血管起着支持和保护的作用，越来越多的研究表明血管外膜的主要成分外膜成纤维细胞能够发挥不同的生物学功能，包括产生和降解细胞外机制，分泌细胞因子，与其他细胞相互作用等调控血管功能。然而，外膜介导的血管炎症分子机制及其致病机理至今尚不明确。在高平进教授的指导下，健康所博士研究生李晓东等研究人员对外膜成纤维细胞中血管内皮生长因子1型受体（Flt-1）介导的血管炎症进行了深入的研究。通过合成特异性的Flt-1多肽抑制剂处理原代外膜成纤维细胞，发现血管内皮生长因子（VEGF）通过激活其受体Flt-1上调骨桥蛋白（OPN）的表达水平。进一步研究发现VEGF调节成纤维细胞对巨噬细胞的趋化活性是依赖于OPN的表达。更重要的是，利用颈动脉球囊模型发现经血管外膜途径局部释放Flt-1多肽抑制剂改善损伤诱导的新生内膜形成，伴随着外膜VEGF和OPN表达的减少，同时侵润损伤血管的巨噬细胞数目也明显减少。研究还发现VEGF是通过激活ERK信号通路促进OPN的表达参与炎症反应的。该研究为Flt-1在心血管疾病中发挥的功能提供了理论依据和潜在的药物治疗靶点，具有重要的临床意义和应用价值。

本研究得到国家自然科学基金委、国家科技部和上海市科委项目的资助。

PMC:

PMID:

Vascular Endothelial Growth Factor-Induced Osteopontin Expression Mediates Vascular Inflammation and Neointima Formation via Flt-1 in Adventitial Fibroblasts.

Li XD, Chen J, Ruan CC, Zhu DL, Gao PJ.

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. CONCLUSIONS: 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.