A MODEL OF ARTERIAL SMOOTH MUSCLE CELL PROLIFERATION TO STUDY RESTENOSIS

最近，相当大的兴趣集中在血管平滑 肌肉细胞（SMC）对损伤的反应，特别是当它涉及到 血管成形术后再狭窄。 我们开发了一种实验性的 动脉平滑肌细胞增殖模型，模拟再狭窄，在 正常胆固醇血症的兔子。 我们发现挤压伤 兔耳中央动脉引起的组织学变化 形态学上类似于再狭窄，我们已经表征了 以前这种病变的自然史。 利用这个模型，我们 已经检查了嵌合融合毒素在体内的作用。 酸性 FGF-PE 664 Glu KDEL（aFGF-PE）是通过连接 编码酸性成纤维细胞生长因子（FGF）的基因， 假单胞菌外毒素 外毒素经过突变 结构域非功能性的，并且融合蛋白在E.杆菌 这种嵌合毒素靶向肿瘤细胞和带有FGF的SMC 受体，并具有强的细胞毒性作用。 以确定是否 aFGF-PE在体内抑制SMC对损伤的增殖反应，我们 研究了动脉挤压损伤后的新生内膜形成， 正常胆固醇血症的兔子 新西兰白色家兔接受挤压 耳中央动脉受伤 兔接受aFGF-PE（10或100 mg）。 30微克/耳，N=31）或安慰剂（N=17），作为1小时动脉内 输注，损伤后1、3、6和9天。 将家兔处死， 第14天，对每个病灶进行测面积。 新生内膜形成是 相当于10和30微克组。 平均新生内膜面积， 以图尼卡中膜面积的百分比表示，为35+/-19% 治疗组家兔中为53+/-37%，对照组为53+/-37%（平均值+/- SD，p=0.05）。 我们 结论是局部施用aFGF-PE抑制新生内膜 在兔原发性动脉损伤后形成。 进一步研究 将有必要确定这些结果是否可以外推 其他动物模型。 需要进一步研究才能确定 aFGF-PE在全身给予时是否发挥有益作用， 当动脉损伤叠加在基础血管上时， 动脉病变

Recently, considerable interest has focused on the vascular smooth muscle cell (SMC) response to injury, particularly as it relates to restenosis following angioplasty. We have developed an experimental model of arterial SMC proliferation, mimicking restenosis, in the normocholesterolemic rabbit. We have found that crush injury to the central artery of the rabbit ear causes histologic changes morphologically similar to that of restenosis, and we have characterized previously the natural history of such a lesion. Using this model, we have examined the effects of a chimeric fusion toxin in vivo. Acidic FGF-PE664Glu KDEL (aFGF-PE) is a fusion protein generated by ligating the genes encoding acidic fibroblast growth factor (FGF) with Pseudomonas exotoxin. The exotoxin is mutated to render its binding domain non-functional, and the fusion protein is expressed in E. coli. This chimeric toxin targets tumor cells and SMC's bearing the FGF receptor in vitro, and has potent cytotoxic effects. To determine if aFGF-PE inhibits SMC proliferation in response to injury in vivo, we studied neointimal formation following arterial crush injury in normocholesterolemic rabbits. New Zealand White rabbits underwent crush injury to the central auricular artery. Rabbits received aFGF-PE (10 or 30 microg/ear, N=31) or placebo (N=17), as one hour intra-arterial infusions, 1, 3, 6, and 9 days after injury. Rabbits were sacrificed on day 14, and each lesion was planimeterized. Neointimal formation was equivalent in the 10 and 30 microg groups. Mean neointimal area, expressed as a percentage of the area of the tunica media, was 35+/-19% in treated rabbits vs. 53+/-37% in controls (mean +/- SD, p=0.05). We conclude that local administration of aFGF-PE inhibits neointimal formation following primary arterial injury in rabbits. Further studies will be necessary to determine whether these results can be extrapolated to other animal models. Further studies will be necessary to determine whether aFGF-PE will exert a salutary effect when given systemically, and when arterial injury is superimposed on an underlying arteriosclerotic lesion.