Intravitreal injection of plasminogen kringle 5, an endogenous angiogenic inhibitor, arrests retinal neovascularization in rats.
OBJECTIVE
Plasminogen kringle 5 is an endogenous angiogenic inhibitor. The purpose of the present study was to explore the potential application of kringle 5 in the treatment of retinal neovascularization.


METHODS
Plasminogen kringle 5 was expressed in E. coli and affinity-purified. Its anti-angiogenic activity was determined in cultured primary human capillary endothelial cells. Retinal neovascularization was induced in newborn rats by exposure to hyperoxia and then normoxia. Kringle 5 was intravitreally injected into the rat model. Retinal neovascularization was visualized by fluorescein angiography on flat-mounted retina and quantified by counting preretinal vascular cells.


RESULTS
Plasminogen kringle 5 inhibited primary endothelial cells but not retinal neuronal cells, suggesting cell type-specific inhibition. The oxygen-induced retinopathy rat model showed an over-expression of vascular endothelial growth factor, preretinal neovascularization and haemorrhage. Intravitreal injection of kringle 5 before the development of neovascularization resulted in fewer neovascular tufts and pre-retinal vascular cells than in control rats with PBS injection (p < 0.01). Moreover, injection of kringle 5 after the development of neovascularization inhibited the increase in the preretinal vascular cells (p < 0.05). These results suggest that kringle 5 both prevents the development and arrests the progression of retinal neovascularization. The injection of kringle 5 did not result in any detectable inflammatory response in the retina or histological toxicity to retina neurons and pre-existing vessels.


CONCLUSIONS
These observations suggest that intravitreal delivery of angiogenic inhibitors could have therapeutic benefits in neovascular diseases of the retina.
Zhang
D
D
Department of Ophthalmology, Medical University of South Carolina, Charleston 29403, USA.
Kaufman
P L
PL
Gao
G
G
Saunders
R A
RA
Ma
J X
JX
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D002196:Capillaries / Q000166:cytology / Q000187:drug effects; D002452:Cell Count; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000473:pathology; D007267:Injections; D018082:Kringles; D009389:Neovascularization, Pathologic / Q000473:pathology* / Q000517:prevention & control*; D009842:Oligopeptides / Q000494:pharmacology; D010100:Oxygen; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D010958:Plasminogen / Q000378:metabolism*; D051381:Rats; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012016:Reference Values; D012160:Retina / Q000187:drug effects / Q000473:pathology; D012164:Retinal Diseases / Q000139:chemically induced; D012171:Retinal Vessels / Q000187:drug effects* / Q000473:pathology; D014822:Vitreous Body
D020533:Angiogenesis Inhibitors; D009842:Oligopeptides; D010446:Peptide Fragments; D011994:Recombinant Proteins; C047981:arginyl-glycyl-aspartic acid; D010958:Plasminogen; D010100:Oxygen