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Plasminogen activator inhibitor (PAI)-1 overexpression in retinal microvessels of PAI-1 transgenic mice
M B Grant1, P E Spoerri, D W Player
1Department of Medicine, University of Florida, Gainesville 32610-0226, USA. grantma@medicine.ufl.edu
Purpose:
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.
Insights
Overexpression of plasminogen activator inhibitor-1 (PAI-1) in retinal microvasculature causes disease similar to diabetic retinopathy. This study used transgenic mice to investigate PAI-1
Area of Science:
- Ophthalmology
- Vascular Biology
- Diabetic Complications
Background:
- Disturbances in plasminogen activator inhibitor-1 (PAI-1) are implicated in diabetic microvascular complications.
- Understanding the role of PAI-1 in retinal disease is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate if PAI-1 overexpression in retinal microvasculature induces a disease phenotype resembling diabetic retinopathy.
- To examine ocular tissue from transgenic mice engineered to overexpress human PAI-1.
Main Methods:
- Transgenic mice were administered zinc sulfate (ZnSO4) to induce human PAI-1 expression.
- Human PAI-1 levels were quantified using immunocytochemistry.
- Retinal microvessels were analyzed for basement membrane thickness and microangiopathy via electron and light microscopy.
Main Results:
- Significant increase in human PAI-1 immunoreactivity in retinal capillaries of zinc-treated transgenic mice.
- Markedly thickened basement membranes in retinal capillaries of PAI-1 overexpressing mice.
- Elevated endothelial cell-to-pericyte ratio observed in the retinal vasculature.
Conclusions:
- PAI-1 overexpression in retinal microvasculature recapitulates key features of diabetic retinopathy.
- PAI-1 is a significant factor in the pathogenesis of diabetic retinal disease.
