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Maria B. Grant, Polyxenie E. Spoerri, Denifield W. Player, David M. Bush, E. Ann Ellis, Sergio Caballero, W. Gerald Robison; Plasminogen Activator Inhibitor (PAI)-1 Overexpression in Retinal Microvessels of PAI-1 Transgenic Mice. Invest. Ophthalmol. Vis. Sci. 2000;41(8):2296-2302.
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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
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