全反式维甲酸对球囊损伤大鼠胸主动脉VSMC表型变化及增殖的影响

INFLUENCE OF ATRA ON PHENO TYPIC MODULATION AND PROLIFERATION OF VSMC IN RATS WITH AORTIC BALLOON INJURY

①目的探讨全反式维甲酸(ATRA)对球囊剥脱大鼠胸主动脉内皮后血管平滑肌细胞(VSMC)表型变化及增殖的影响。②方法雄性SD大鼠54只,随机分为3组。ATRA治疗组(n=24)行球囊剥脱大鼠胸主动脉内皮术,术前4d开始予ATRA芝麻油混悬液(30mg.kg-1.d-1)灌胃至术后处死;手术组(n=24)行球囊剥脱大鼠胸主动脉内皮术,术前4d开始予芝麻油(1mL.kg-1.d-1)灌胃至术后处死;对照组(n=6)除不插入球囊导管外,其他操作同手术组。分别于术后2、7、14、28d取胸主动脉应用苏木精-伊红染色、免疫组化和计算机图像分析法进行形态学、平滑肌α肌动蛋白(SM--αactin)和增殖细胞核抗原(PCNA)表达水平检测。③结果正常动脉VSMC高表达SM--αactin,处于非增殖状态;损伤后中膜SM--αactin表达迅速下降,2d达最低水平,而增殖旺盛,后趋向正常水平;新生内膜在术后7d出现,处于高度增殖状态,SM--αactin含量少,术后14、28d的SM--αactin表达明显增多,而增殖下降。ATRA治疗能明显抑制中膜SM--αactin的下调,诱导内膜和中膜SM--αactin表达,显著抑制VSMC的迁移和增殖,明显抑制新生内膜形成和管腔缩窄。SM--αactin表达与PCNA表达呈显著负相关(r=-0.738,P<0.01)。④结论维持并诱导VSMC于较高的分化状态,抑制VSMC迁移和增殖,是ATRA抑制球囊损伤大鼠主动脉后新生内膜增生和管腔狭窄的可能机制之一。

Objective To investigate the influence of all-trans retinoic acid（ATRA） on phenotypic modulation and proliferation of vascular smooth muscle cell （VSMC） in rats following aortic balloon injury. Methods Fifty-four SD rats were randomly divided into three groups： Control group （n=6）, Operation group （n=24） and at RA group（n=24）. The rats in the ATRA group had balloon induced endothelium denudation at thoracic aorta and were killed at 2, 7, 14, and 28 days after the injuries. After each procedure the thoracic aorta were harvested, immunohistoehemistry staining used to measure the protein expression of differentiated phenotypic maker SM-α-actin and proliferation cell nuclear antigen PCNA. Vessel morphological measurement was taken. Results In normal rat arteries, SM-α-actin expressed abundantly. After injury, the expression of SM-α-actin was down regulated quickly, and reached the lowest on day two, while VSMC proliferation increased markedly and then trended toward the normal level. Newly born tunica intima appeared on day seven, VSMC being in extreme proliferation, the content of SM-α-actin declined. On day 14 and 28, the expression of SM-α-aetin increased obviously while proliferation decreased. ATRA could markedly suppressed the down regulation of in tunica media, induce SM-α-actin expression both in tunica media and tunica intima, strongly inhibit the migration and proliferation of VSMC and formation of new blood vessels as well as to restrain the constriction of the lumen of blood vessel. The expression of SM-α-aetin and the cell proliferation （PCNA） was in remarkable negative correlation （r=-0. 738, P〈0.01）. Conclusion Inhibiting the proliferation of VSMC by maintaining and inducing more differentiated VSMC may be one of the mechanisms that ATRA reduces the formation of newly born tunica intima and constriction of blood lumen after balloon injury of rat aortic artery.