Low content of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor predicts progression of diabetic retinopathy

Aims/hypothesis. Retinopathy is the most common microvascular complication of diabetes. Our aim was to address the predictive value of pro-angiogenic and anti-angiogenic markers for progression of retinopathy. Methods. Aqueous humor was collected at cataract surgery from 32 diabetic patients who had no or very mild retinopathy (ETDRS stage less than or equal to20) and 33 normoglycaemic control subjects. Content of pro-angiogenic vascular endothelial growth factor and angiogenic inhibitor pigment epithelium-derived factor were determined. Angiogenic activity was quantified by measuring its effect on the migration of capillary endothelial cells. The predictive value of the initial level of these markers for progression of retinopathy was studied by following the probands for a maximum of 75 months. Results. In the aqueous fluid content of vascular endothelial growth factor was increased in diabetic patients (mean values 492 versus 292 pg/ml; p=0.0052), and pigment epithelium-derived factor values were decreased (mean values 1740 versus 3680 ng/ml; p=0.0058) compared to control subjects. Of the diabetic patients ten progressed during follow-up (ETDRS stage >47B). This subgroup showed lower pigment epithelium-derived factor content when compared to non-progressors and control subjects. Migratory activity in samples of patients from the control group and in diabetic patients without progression was generally inhibitory due to pigment epithelium-derived factor. Inhibition was blocked by neutralizing antibodies to pigment epithelium-derived factor. In diabetic patients initial angiogenic activity was higher in those who later developed retinopathy (vs. controls p=0.00005; vs. no progressors p=0.0003). Both pigment epithelium-derived factor and migratory response predicted progression. Conclusion/Interpretation. Pigment epithelium-derived factor is an important negative regulator of angiogenic activity of aqueous humor. Its content in the aqueous humor of diabetic patients strongly predicts who among them will develop progression of retinopathy.