血小板衍生生长因子BB激活细胞外信号调节激酶1/2参与血管新生内膜形成  

Platelet-derived growth factor BB activates extracellular signal-regulated kinases 1/2 contributing to neointimal formation

作　　者：陈静[1] 李晓东[2] 洪墨纳[2] 高平进[1,2] 

机构地区：[1]上海交通大学医学院附属瑞金医院北院高血压科,上海201801 [2]上海交通大学医学院附属瑞金医院高血压科,上海市高血压研究所

出　　处：《中华高血压杂志》2016年第12期1147-1153,共7页Chinese Journal of Hypertension

基　　金：国家自然科学基金青年科学基金项目(81400191)

摘　　要：目的血小板衍生生长因子BB(PDGF-BB)是介导血管新生内膜形成最重要的生长因子之一,本研究探讨PDGF-BB激活细胞外信号调节激酶1/2(ERK1/2)参与血管新生内膜的形成。方法在整体实验上,将24只250g健康雄性SD大鼠分为3组:A组为假手术组;B组为颈动脉球囊损伤组;C组为颈动脉球囊损伤干预组(ERK1/2抑制剂PD98059)。建立颈动脉球囊损伤模型后,经血管外膜途径局部给予PD98059抑制ERK1/2激活,苏木精-伊红(HE)染色分析损伤血管形态学变化,免疫荧光检测巨噬细胞浸润。原代培养外膜成纤维细胞,Western blot检测细胞ERK1/2的激活,划痕实验观察细胞迁移变化。结果损伤组新生内膜面积和内膜中膜比大于干预组[(0.149±0.012)比(0.077±0.021)mm2,1.137±0.088比0.682±0.141,均P<0.01]。损伤组管腔面积小于干预组[(0.249±0.021)比(0.314±0.016)mm^2,P<0.05]。同时,PD98059能明显改善新生内膜形成,伴随巨噬细胞浸润明显减少。20μg/L PDGF-BB瞬时激活ERK1/2在5min时磷酸化ERK1/2表达最高,并且ERK1/2的激活能够被PD98059所抑制。PD98059也抑制PDGF-BB促进外膜成纤维细胞的迁移。结论经外膜干预ERK1/2激活可以改善损伤诱导的新生内膜形成,可能是通过抑制PDGF-BB介导的外膜成纤维细胞的迁移。Objective Platelet-derived growth factor BB（PDGF-BB）plays an important role in neointimal formation. In this study,we sought to determine the effect of extracellular signal-regulated kinases 1/2（ERK1/2）activated by PDGF-BB on vascular neointimal formation. Methods Twenty-four male Sprague-Dawley（SD）rats weighing 250 grams were divided into three groups：Group A,sham;Group B,balloon injury,Group C,balloon injury plus PD98059. After balloon injury,perivascular delivery of PD98059 was used to suppress ERK1/2 activation.Hematoxylin-eosin（HE）staining was used to analyze the morphological changes of the injured arteries. Macrophage infiltration was detected by immunofluorescence. In primary culture adventitial fibroblasts,ERK1/2 activation was evaluated by Western blot. Wound scratch assay was used to analyze the migration of adventitial fibroblasts.Results Neointimal area and intima/media ratio in balloon injury group were higher than that in balloon injury plus PD98059 group [（0.149±0.012）vs（0.077±0.021）mm2,1.137±0.088 vs 0.682±0.141,both P0.01],while lumen area was lower in balloon injury group than balloon injury plus PD98059group[（0.249±0.021）vs（0.314±0.016）mm^2,P〈0.05]. Compared with balloon injury group,PD98059 significantly attenuated neointimal formation,which was associated with decrease of macrophage infiltration.20μg/L PDGF-BB enhanced ERK1/2 activation with peak at 5 min,and this effect was blocked by PD98059. PD98059 also suppressed PDGF-BB induced migration of adventitial fibroblasts. Conclusion Blockade of ERK1/2 activation attenuates injury-induced neointimal formation,which might through PDGF-BB induced migration of adventitial fibroblasts.

关 键 词：外膜成纤维细胞 新生内膜形成 细胞外信号调节激酶1/2 

分 类 号：R543[医药卫生—心血管疾病]