Inhibition of retinal neovascularization by intravitreal injection of human rPAI-1 in a rat model of retinopathy of prematurity.
OBJECTIVE
Restructuring of extracellular matrix at actively extending blood vessel tips involves secretion of plasminogen activator (PA). Findings in earlier studies conducted in the authors' laboratory have suggested that angiostatic steroids suppress the PA activity essential for the invasive aspect of angiogenesis by increasing synthesis of plasminogen activator inhibitor (PAI)-1. This experiment was designed to test the effect of administration of exogenous PAI-1 on retinal neovascularization (NV) in an animal model of retinopathy of prematurity (ROP).


METHODS
At birth, Sprague-Dawley rats were placed into incubators and exposed to an atmosphere alternating between 50% and 10% O(2) every 24 hours. After 14 days, the animals were removed to room air, at which time each received a single intravitreal injection of 5 microL of buffer vehicle or one of five doses of PAI-1, ranging from 3.0 microg/mL to 2.0 mg/mL. Animals were killed 6 days later, and retinal NV was assessed using adenosine diphosphatase (ADPase) histochemical staining.


RESULTS
Retinal neovascularization decreased with increasing PAI-1 dosage. The most effective dose tested (2.0 mg/mL) caused a 52% reduction in retinal NV relative to vehicle (P < 0.005). Normal vasculogenesis, as determined by measuring retinal vascular area, was unaffected.


CONCLUSIONS
PAI-1 inhibits pathologic angiogenesis without adversely affecting normal vasculogenesis, an attractive feature for ROP therapies. Moreover, PAI's relationship to matrix metalloproteinases, which are also implicated in angiogenesis, suggests that the proteolytic aspect of the process may provide additional downstream therapeutic targets.
Penn
John S
JS
Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, 2115 21st Avenue South, 8016 Medical Center East, Nashville, TN 37232-8808, USA. john.penn@vanderbilt.edu
Rajaratnam
Veera S
VS
D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007267:Injections; D017395:Plasminogen Activator Inhibitor 1 / Q000627:therapeutic use*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D015861:Retinal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012178:Retinopathy of Prematurity / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D014822:Vitreous Body
D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D014568:Urokinase-Type Plasminogen Activator; D018093:Gelatinases