VASCULAR ENDOTHELIAL GROWTH-FACTOR AND VASCULAR-PERMEABILITY CHANGES IN HUMAN DIABETIC-RETINOPATHY

Purpose. The authors used histochemical analysis to determine whether increased vascular endothelial growth factor (VEGF) immunoreactivity i n diabetic retinal vessels is related to increased vascular permeabili ty, as indicated by human serum albumin (HSA) immunostaining, or to pr esumed retinal hypoxia, as demonstrated by decreased vascularity. A co rrelation between VEGF and HSA in cryosections with angiopathic change s in the adenosine diphosphatase (ADPase) fiat-embedded fellow retinas was sought. Because VEGF is a heparin-binding protein, the relation b etween VEGF and heparan sulfate proteoglycan (HSPG) immunoreactivities was also investigated. Methods. Cryopreserved eyes from 18 diabetic a nd 9 nondiabetic subjects removed after death were sectioned and immun ohistochemical analysis was performed with antibodies against VEGF, HS A, HSPG, vWf (von Willebrand factor), and collagen IV. The fellow reti nas were prepared by our ADPase flat-embedding technique to determine the degree of diabetic retinopathy. The number of positive vessels for each antibody and antibody localizations were determined by light mic roscopy. Results. The average number of VEGF-stained vessels in diabet ic retinas was significantly higher than in nondiabetic retinas (P = 0 .04). In diabetic retinas, there was a positive correlation between th e distribution of VEGF-positive vessels and the distribution of HSA- a nd HSPG-positive vessels. No such correlation was observed in nondiabe tic eyes. In many cases, HSPG immunoreactivity appeared colocalized wi th VEGF immunoreactivity,suggesting VEGF binding to HSPG. The comparis on with the ADPase flat-embedded fellow retinas suggested that increas ed VEGF immunoreactivity and vascular permeability may occur before mo rphologic changes in the vasculature. Conclusions. Vascular endothelia l growth factor immunoreactivity was correlated with increased vascula r permeability to macromolecules and appears to be increased in diabet ic subjects before the onset of retinopathy.