Plasminogen activator inhibitor (PAI)-1 overexpression in retinal microvessels of PAI-1 transgenic mice.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
PAI-1 overexpression in retinal microvasculature leads to retinal disease similar to that observed in diabetic retinopathy.
Grant
M B
MB
Department of Medicine, University of Florida, Gainesville 32610-0226, USA. grantma@medicine.ufl.edu
Spoerri
P E
PE
Player
D W
DW
Bush
D M
DM
Ellis
E A
EA
Caballero
S
S
Robison
W G
WG
D000818:Animals; D001485:Basement Membrane / Q000378:metabolism / Q000648:ultrastructure; D002196:Capillaries; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D020286:Pericytes / Q000378:metabolism / Q000648:ultrastructure; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D012171:Retinal Vessels / Q000378:metabolism* / Q000648:ultrastructure; D015842:Serine Proteinase Inhibitors / Q000096:biosynthesis* / Q000235:genetics; D019287:Zinc Sulfate / Q000008:administration & dosage
D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors; D019287:Zinc Sulfate