A MODEL OF ARTERIAL SMOOTH MUSCLE CELL PROLIFERATION TO STUDY RESTENOSIS

用于研究再狭窄的动脉平滑肌细胞增殖模型

• 批准号: 3858120
• 负责人: E UNGER
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3858120
• 关键词: artery stenosis; atherosclerosis; cell growth regulation; disease /disorder model; histopathology; intraluminal angioplasty; laboratory rabbit; protein engineering; relapse /recurrence; vascular smooth muscle

Recently, considerable interest has focused on the vascular smooth muscle cell (SMC) response to injury, particularly as it relates to restenosis following angioplasty. In order to find an optimal experimental model of arterial SMC proliferation following injury, we examined the effects of external injury to the central artery of the rabbit ear, and assessed the reproducibility, morphologic changes, and time course of cellular proliferation following such an injury. Under general anesthesia, direct pressure was applied at two sites along the central artery of the ears of 16 New Zealand white rabbits. Rabbits were maintained on a 2.4% fat, 0.001% cholesterol diet throughout the experiment. In 7 rabbits examined after 21 days, marked SMC proliferation with neointimal formation was observed at all 28 sites (100%). Mean neointimal area, expressed as a percentage of the area of the tunica media, was 82+/-40% (range 21% to 203%). Compared to the uninvolved artery displaced 2 mm from the injury site, mechanical injury caused a 38% increase in total vessel area (p<0.001), a 40% decrease in luminal area (p<0.002), and no change in the area of the media. Serial histologic studies were performed 1 to 42 days after injury, using light and electron microscopy and bromodeoxyuridine immunohistochemistry. Beginning at day 3, activated medial SMC's were noted to migrate through defects in the internal elastic membrane, with a gradual increase in neointimal area between days 5 and 12. Peak DNA synthesis occurred in the media 5 days post injury, with proliferative activity shifting almost exclusively to the neointima thereafter. We conclude that mechanical injury is a potent stimulus for SMC proliferation. The method is simply employed, multiple lesions can be created in a single animal with high yield, and therapeutic endpoints can be easily quantified. The lesions so produced are superficial and easily accessible; therefore, agents with the potential to prevent SMC proliferation can be targeted locally by subcutaneous injection or topical application.

近年来，人们对血管平滑肌的研究引起了很大的兴趣 细胞（SMC）对损伤的反应，特别是与再狭窄相关时 血管成形术后 为了找到一个最佳的实验模型， 动脉平滑肌细胞增殖损伤后，我们检查的影响， 外部损伤兔耳中央动脉，并评估 重复性、形态学变化和细胞的时程 这种损伤后的扩散。 在全身麻醉下，直接 压力施加在两个部位沿着中央动脉的耳朵 16只新西兰白色家兔。 兔子维持在2.4%的脂肪， 0.001%胆固醇饮食。 在7只检查的家兔中 21天后，平滑肌细胞明显增生，并有新生内膜形成， 在所有28个研究中心均观察到（100%）。 平均新生内膜面积，表示为 图尼卡中膜面积的百分比为82+/-40%（范围21%至 203%）。 与未受累动脉相比， 机械损伤导致总血管面积增加38% （p<0.001），管腔面积减少40%（p<0.002）， 媒体领域。 在1至42天内进行了系列组织学研究 损伤后，使用光镜和电镜以及溴脱氧尿苷 免疫组化 从第3天开始，活化的中膜SMC被 注意到通过内部弹性膜中的缺陷迁移， 新生内膜面积在第5 - 12天逐渐增加。 DNA峰 损伤后5天，在培养基中发生合成， 此后活动几乎完全转移到新生内膜。 我们 结论：机械损伤是SMC的一个强有力的刺激 增殖 该方法使用简单，可同时切除多个病灶， 在单个动物中以高产量产生，并且治疗终点可以 很容易量化。 这样产生的损伤是表面的， 因此，有可能预防SMC的药物 可以通过皮下注射局部靶向增殖， 局部应用。