组织型纤溶酶原激活物及其抑制剂对血管平滑肌细胞增生迁移的作用及其有关机制

【作者】 马晓莉；

【导师】 佘铭鹏； 黄文英；

【作者基本信息】 中国协和医科大学 ， 病理学， 1997， 博士

【摘要】 动脉粥样硬化(AS)作为导致脑梗塞、心肌梗塞、肢端坏疽，以及器官或组织功能丧失的主要病因，是引起死亡的主要原因之一。近十年来，经皮冠脉腔内成形术(PTCA)成为治疗冠状动脉粥样硬化疾病的常用手段。随着临床经验的积累及仪器设备的完善，临床应用越来越广泛。然而术后高达30-50％的再狭窄率仍是目前亟待解决的难题，也是PTCA进一步推广应用的一大障碍。血管平滑肌细胞(SMC)从中膜向内膜迁移以及在内膜、中膜增生在AS形成及PTCA术后再狭窄过程中都起着重要作用。血小板、内皮细胞、激活的单核细胞、SMC本身均可释放一些生长因子和细胞介质，例如：PDGF、bFGF、EGF、IGF-1等并通过相互协调，促进SMC的增生和迁移。尽管对SMC增生和迁移的机制已进行了大量的研究，但目前仍未十分清楚。一些研究提出纤溶酶原激活物(PAs)系统可能也参与SMC的增生和迁移。PAs是纤溶系统的主要成分，包括组织型(tPA)和尿激酶型(uPA)两种类型，其主要功能是使纤溶酶原转化成纤溶酶，纤溶酶使纤维蛋白和很大一部分细胞外基质成分降解，且使胶原酶原激活转变成胶原酶。虽然PAs对肿瘤细胞和其他一些细胞的作用已有所研究，但近年来Clowes等才在球囊损伤的鼠颈动脉壁观察到PAs表达，并认为可能与SMC的增生和迁移有关。动物实验显示PDGF，AngⅡ，PMA等均可刺激动脉壁PAs表达增加。近年来对动物和人的动脉壁及动脉粥样硬化斑块部位有关PAs和PAI-1的分布虽已进行了不少研究，但对PAs，PAI-1与血管SMC增生的关系仍很不清楚，一些研究结果也不完全一致。 本项研究首先建立兔髂动脉损伤模型，用Fogarty球囊导管造成血管内皮剥脱，观察损伤前后血管壁结构的改变；在损伤前后测定血管壁tPA活性变化；以tPA cDNA为探针进行原位分子杂交，观察tPA与血管SMC增生和迁移的关系。研究发现在内皮剥脱后第4天，中膜SMC开始向内膜迁移，第7天，内膜已较明显增厚，以SMC成分为主。内皮剥脱导致中膜提取物中tPA活性明显升高，tPA活性的变化与tPA mRNA表达水平的变化一致。提示tPA活性的升高可能与更多还原

【Abstract】 Atherosclerosis (AS) is known as the main cause of inducing the development of cerebral thrombosis, myocardial infarction, and gangrene of the extremities, accompanied with a very high mortality. Percutaneous transluminal coronary angioplasty (PTCA) has been adopted as a measure for the treatment of coronary atherosclerotic diseases since last decade. Increased experience in practice and improvement of the equipments, facilities as well as the consummation of indications have led PTCA to be more and more expanded in clinical application. However, the high incidence of restenosis following 30-50% of initially successful procedures remains the major problem to be resolved. It’s considered that migration and proliferation of vessel smooth muscle cell (SMC) play a predominant role in the development of restenosis. Growth factors and cytokines, such as PDGF, bFGF, E:GF, IGF-1, released from platelets, endothelial cells, activated monocytes and SMC, work together and stimulate SMC undergoing migration and proliferation. Although a lot of studies have been carried out, anyhow, the mechanism of SMC migration and proliferation in case of restenosis still remains not well understood.Data of recent investigations have suggested that plasminogen activators (PAs) system may play an important role in this process. Plasminogen activators, including tissue-type plasminogen activator(tPA) and urokinase-type plasminogen activator (uPA), are the major parts of fibrinolytic system. The principal function of these two plasminogen activators is to convert plasminogen to plasmin. Plasmin in turn degrades not only fibrin but also a broad range of extracellular matrix molecules. It also activates procollagenase to collagenase. Even though the effects of PAs on tumor and other cells have been studied and published, Clowes et al provided initial evidence for the expression of PAs in a balloon-injured rat carotid artery only更多还原