Deficient activation and different expression of transforming growth factor-beta isoforms in active proliferative diabetic retinopathy and neovascular eye disease

An increased expression and secretion of angiogenic growth factors was prop osed to occur in proliferative diabetic retinopathy and other neovasculariz ing retinal diseases. However, a loss of anti-angiogenic factors also might promote retinal neovascularization. Therefore we investigated the active a nd latent vitreous levels of the subtypes of the endothelial anti-mitogen t ransforming growth factor-beta in vitreous of 58 patients. Four groups of p atients were compared: Controls without retinal hypoxia, patients with quie scent and active proliferative diabetic retinopathy (PDR), and patients wit h severe retinal hypoxia resulting in rubeosis iridis. Whereas the amount o f total TGF-beta in the four groups did not differ significantly, latent TG F-beta isoform expression showed complex alterations in ocular vitreous. Le vels of active TGF-beta off patients with active PDR (79.5 +/- 28 pg/ml; n = 8) were decreased to 20% of the control levels (378 +/- 55 pg/ml; n = 12; p = 0.0005) and 25% of the mean concentration in quiescent PDR (346 +/- 64 pg/ml; n = 9; p = 0.0021). Levels in rubeosis (52 +/- 10 pg/ml; n = 10) di d; not differ significantly from those found in active PDR but were decreas ed to 15 % of those in patients with quiescent PDR (p = 0.0004). Furthermor e a highly significant inverse correlation between active TGF-beta and alph a(2)-antiplasmin, a liver produced inhibitor of the activation of TGF-beta by plasmin was noted (r = -0.59; n = 28; p = 0.001). We conclude that defic ient activation of TGF-beta occurs in active proliferative diabetic retinop athy and in hypoxic angiogenesis most likely as a consequence of a blood re tina barrier breakdown and influx of alpha(2)-antiplasmin from serum. The d isinhibition of endothelial cell proliferation may be a central component i n the process of neovascularization.