血管紧张素Ⅱ受体Ⅰ阻滞剂抑制血管平滑肌细胞增殖、迁移的实验研究

Inhibitory effects of angiotensin type 1 receptors antagonist on vascular smooth muscle cells proliferation and migration in rabbit carotid injury model

目的:观察血管紧张素Ⅱ受体Ⅰ阻滞剂Valsartan对家兔颈动脉球囊损伤模型动脉中膜血管平滑肌细胞增殖、迁移的抑制作用。方法:健康家兔制作颈动脉球囊损伤模型,随机分为对照组(n=10)和Valsartan治疗组(n=10),治疗组术后予Valsartan喂食,10mg/(kg·d),共10天,对照组正常喂食。各组动物术前和术后3天、1、2、4、8周留取静脉血,放免法检测内皮素(ET-I);术后4、8周每组随即处死动物5只,HE染色、原位标记凋亡细胞(TUNEL)和增殖细胞核抗原(PCNA)免疫组化染色,应用光学显微镜和计算机图像分析系统对切片进行图像分析。结果:术后3天、1、2、4、8周治疗组血浆ET-1水平低于对照组(P<0.01);术后4周和8周治疗组血管壁平滑肌细胞凋亡率高于对照组,PCNA阳性率低于对照组(P<0.05);动脉内膜、中膜厚度和面积小于对照组(P<0.01);残余管腔面积大于对照组(P<0.01)。结论:血管紧张素Ⅱ受体Ⅰ阻滞剂Valsartan可以抑制内膜受损动脉中膜平滑肌细胞增殖和向内膜迁移,并促进其凋亡,预防受损动脉内膜过度增生,管腔狭窄。

Objective： To investigate the effects of Angiotensin type 1 receptors antagonist （Valsartan） on the proliferation and migration of vascular smooth muscle cells and neointimal thickening in rabbit carotid injury model. Methods： Twenty rabbits undergoing ballon-induced injuries in right common carotids were randomly divided into control group （n = 10）and Valsartan-treated group （n = 10）.Rabbits in the late group were administrated with Valsartan 10 mg/（kg·d） plus normal food and water for 10 days. Changes of the levels of plasma endothelin-1 （ET-1 ）were measured by radioimmunoassay before operation and 3 days, 1,2,4,8 weeks after operation respectively. Four weeks and 8 weeks after operation ,5 rabbits of each group were killed and the segments of balloninjuried carotids were harvested for pathomorphological examination. The vessels were processed to examine VSMCs proliferation by hematoxylin-eosin staining, proliferation cell nuclear antigen （PCNA）immunohistochemistry staining and apoptotic body staining by terminal deocynucleotidyl transferase mediated dUPT nick-end labeling （TUNEL）. Results： The plasma levels of ET-I increased after injury. Valsartan lowed them significantly （P 〈 0.01 ）.Compared with the control group, VSMCs proliferation in medial was significantly inhibited and VSMCs apoptoese was significantly increased in.Valsartan-treated group （P〈 0.01）.Neointimal thickening was observed in all ballon-injuied vessels. Valsartan significantly reduced the neointimal thickening and increased the lumen area （P 〈 0.01）. Conclusion： Angiotensin type 1 receptors antagonist has remarkable inhibiting effects on VSMCs proliferation and migration, resulting in attenuating neointimal thickening in rabbit carotid injury model.