Grant M B, Spoerri P E, Player D W, Bush D M, Ellis E A, Caballero S, Robison W G
Department of Medicine, University of Florida, Gainesville 32610-0226, USA.
Invest Ophthalmol Vis Sci. 2000 Jul;41(8):2296-302.
Previous studies have suggested that disturbances in plasminogen activator inhibitor (PAI)-1 may be relevant to the development of diabetic microvascular complications. To determine whether overexpression of PAI-1 in cells of retinal microvasculature would result in a disease similar to that observed in diabetes, ocular tissue from transgenic mice that overexpress human PAI-1 were examined.
Transgenic mice were administered ZnSO4 (25 mM) in their water for up to 49 weeks to activate the metallothionein promoter and stimulate human PAI-1. Colloidal gold immunocytochemistry was used to quantify the human PAI-1 antigen at 7, 20, 34, and 49 weeks of ZnSO4 administration. Cross sections of retinal microvessels were examined by electron microscopy for changes in basement membrane (BM) thickness. Retinal digest preparations were examined by light microscopy for possible microangiopathy, including changes in endothelial cell-to-pericyte ratios.
Human PAI-1 immunoreactivity was detected throughout the retinal capillaries of transgenic mice receiving zinc and increased significantly (P < 0.001) after 20 to 49 weeks of ZnSO4 administration compared with age-matched transgenic control mice. At 20 and 49 weeks, retinal capillaries of transgenic mice that received zinc showed significantly thickened BMs compared with control animals (P < 0.001). Moreover, wholemounts of the retinal vasculature from PAI-1 transgenic mice demonstrated an increased endothelial cell-to-pericyte ratio.
PAI-1 overexpression in retinal microvasculature leads to retinal disease similar to that observed in diabetic retinopathy.
以往研究表明，纤溶酶原激活物抑制剂（PAI）-1紊乱可能与糖尿病微血管并发症的发生有关。为了确定视网膜微血管细胞中PAI-1的过表达是否会导致与糖尿病中观察到的疾病相似的疾病，对过表达人PAI-1的转基因小鼠的眼组织进行了检查。
给转基因小鼠在饮水中给予硫酸锌（25 mM）长达49周，以激活金属硫蛋白启动子并刺激人PAI-1。采用胶体金免疫细胞化学法在给予硫酸锌的第7、20、34和49周定量人PAI-1抗原。通过电子显微镜检查视网膜微血管的横断面，观察基底膜（BM）厚度的变化。通过光学显微镜检查视网膜消化制剂，观察是否存在微血管病变，包括内皮细胞与周细胞比例的变化。
在接受锌的转基因小鼠的整个视网膜毛细血管中检测到了人PAI-1免疫反应性，与年龄匹配的转基因对照小鼠相比，在给予硫酸锌20至49周后显著增加（P<0.001）。在第20和49周时，接受锌的转基因小鼠的视网膜毛细血管的BM与对照动物相比显著增厚（P<0.001）。此外，PAI-1转基因小鼠视网膜血管的整装标本显示内皮细胞与周细胞的比例增加。
视网膜微血管中PAI-1的过表达导致类似于糖尿病视网膜病变中观察到的视网膜疾病。
