VASCULAR ENDOTHELIAL GROWTH FACTOR-INDUCED RETINAL PERMEABILITY IS MEDIATED BY PROTEIN-KINASE-C IN-VIVO AND SUPPRESSED BY AN ORALLY EFFECTIVE BETA-ISOFORM-SELECTIVE INHIBITOR

Increased vascular permeability and excessive neovascularization are t he hallmarks of endothelial dysfunction, which can lead to diabetic ma cular edema and proliferative diabetic retinopathy in the eye. Vascula r endothelial growth factor (VEGF) is an important mediator of ocular neovascularization and a known vasopermeability factor in nonocular ti ssues. In these studies, we demonstrate that intravitreal injection of VEGF rapidly activates protein kinase C (PKC) in the retina at concen trations observed clinically, inducing membrane translocation of PKC i soforms alpha, beta(II), and delta and >threefold increases in retinal vasopermeability in vivo. The effect of VEGF on retinal vascular perm eability appears to be mediated predominantly by the beta-isoform of P KC with >95% inhibition of VEGF-induced permeability by intravitreal o r oral administration of a PKC beta-isoform-selective inhibitor that d id not inhibit histamine-mediated effects. These studies represent the first direct demonstration that VEGF can increase intraocular vascula r permeability through activation of PKC in vivo and suggest that oral pharmacological therapies involving PKC beta-isoform-selective inhibi tors may prove efficacious for the treatment of VEGF-associated ocular disorders such as diabetic retinopathy.