Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective β-isoform-selective inhibitor

• Published in: Diabetes (New York, N.Y.) Vol. 46; no. 9; pp. 1473 - 1480
• Main Authors: AIELLO, L. P, BURSELL, S.-E, SMITH, L. E. H, KING, G. L, CLERMONT, A, DUH, E, ISHII, H, TAKAGI, C, MORI, F, CIULLA, T. A, WAYS, K, JIROUSEK, M
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-09-1997
• Subjects: Animals; Biological and medical sciences; Capillary Permeability; Cattle; Cells, Cultured; Diabetic retinopathy; Endothelial Growth Factors - physiology; Enzyme Inhibitors - pharmacology; Eye; Eye - blood supply; Growth factors; Indoles - pharmacology; Isoenzymes - antagonists & inhibitors; Isoenzymes - physiology; Lymphokines - physiology; Maleimides - pharmacology; Medical sciences; Pharmacology. Drug treatments; Physiological aspects; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - physiology; Protein kinases; Rats; Retina - enzymology; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Endocrinopathy; Endothelial cell; Molecular form; Protein kinase C; Retinopathy; Rat; Retina; Eye; Visual system; Blood vessel; Complication; Enzyme; Intravitreous administration; Transferases; Diabetes mellitus; Rodentia; Oral administration; Permeability; In vitro; In vivo; Eye disease; Vertebrata; Mammalia; Vascular endothelium growth factor; Treatment; Animal
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diab.46.9.1473

Increased vascular permeability and excessive neovascularization are the hallmarks of endothelial dysfunction, which can lead to diabetic macular edema and proliferative diabetic retinopathy in the eye. Vascular endothelial growth factor (VEGF) is an important mediator of ocular neovascularization and a known vasopermeability factor in nonocular tissues. In these studies, we demonstrate that intravitreal injection of VEGF rapidly activates protein kinase C (PKC) in the retina at concentrations observed clinically, inducing membrane translocation of PKC isoforms alpha, betaII, and delta and >threefold increases in retinal vasopermeability in vivo. The effect of VEGF on retinal vascular permeability appears to be mediated predominantly by the beta-isoform of PKC with >95% inhibition of VEGF-induced permeability by intravitreal or oral administration of a PKC beta-isoform-selective inhibitor that did not inhibit histamine-mediated effects. These studies represent the first direct demonstration that VEGF can increase intraocular vascular permeability through activation of PKC in vivo and suggest that oral pharmacological therapies involving PKC beta-isoform-selective inhibitors may prove efficacious for the treatment of VEGF-associated ocular disorders such as diabetic retinopathy.