PLASMINOGEN ACTIVATOR REGULATION IN INTIMAL HYPERPLASIA

内膜增生中纤溶酶原激活剂的调节

• 批准号: 2444977
• 负责人: SHUNICHIRO S OKADA
• 金额: $ 8.37万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2444977
• 关键词: atherosclerosis; blood vessel disorder; cell growth regulation; cell migration; coronary disorder; enzyme activity; enzyme linked immunosorbent assay; fibroblast growth factor; heart revascularization; heparin; human tissue; hyperplasia; immunocytochemistry; in situ hybridization; interleukin 1; messenger RNA; northern blottings; plasminogen activator; plasminogen activator inhibitors; platelet derived growth factor; receptor expression; restenosis; tissue /cell culture; urokinase; vascular smooth muscle; western blottings

Vascular smooth muscle cells (SMC), when stimulated by vascular injury, contribute to the development of intimal hyperplasia by migrating from the media to the intima, and subsequently, by proliferating in the intima. Plasminogen activators (PA) are a class of fibrinolytic molecules that also facilitate the movement of cells through tissue barriers and extracellular matrix. The enzymatic activity of both types of PA, tissue-type (t-PA) and urokinase-type (u-PA), is regulated in part through the expression of specific cell surface receptors and by plasminogen activator inhibitor type 1 (PAL-1). Recent data in vascular injury models have demonstrated increased expression of PA in temporal association with SMC proliferation and migration. More recently, it has been demonstrated that complexes of PA and PAL-1 become internalized via the alpha2-macroglobulin receptor/low density lipoprotein receptor-related protein (LRP). This process may be important in clearing inactive protease complexes and aiding cell migration. The major long term objective of this proposal is to further investigate the biological significance of the plasminogen activator system in vascular SMC during health and following vascular injury. Preliminary data suggests that SMC cultured from various adult human vascular sources express u-PAR in culture and that u-PAR protein and mRNA expression can be regulated. We will study the expression of u-PAR protein in response to pDGF, bFGF, interleukin-1, and heparin using radioligand binding studies, ELISA, and Western blot analysis. We will determine the steady state level of u-PAR mRNA in response to these agonists by Northern blot analyses. We will study whether or not these agonists affect the capacity of SMC to internalize and degrade radiolabeled u=PAL-1. We will study the effect of exogenously added u-PA or uPA/PAI-1 complexes on: a) SMC migration, using a linear under-agarose assay, and b) SMC proliferation, using both a quantitative cell protein assay and a 3H-thymidine incorporation assay. Finally, we will compare the expression of u-PAR protein and mRNA in vascular SMC using immunohistochemistry and in situ hybridization, respectively, in normal and diseased coronary tissues. Identification of the factors that regulate plasminogen activation system in health and disease may facilitate the development of a biological interventional approach to the prevention or treatment of intimal hyperplasia.

项目成果

Migrating vascular smooth muscle cells polarize cell surface urokinase receptors after injury in vitro.

体外损伤后，迁移的血管平滑肌细胞使细胞表面尿激酶受体极化。

• DOI: 10.1006/excr.1995.1077
• 发表时间: 1995
• 期刊: Experimental cell research
• 影响因子: 3.7
• 作者: Okada,SS;Tomaszewski,JE;Barnathan,ES
• 通讯作者: Barnathan,ES