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

• DOI: 10.2337/diab.46.9.1473
• Publication Date: 2013-09-19T17:42:54Z
• Authors: Lloyd Paul Aiello; Sven-Erik Bursell; Allen Clermont; Elia Duh; Hidehiro Ishii; Chikako Takagi; Fumi Mori; Thomas A Ciulla; Kirk Ways; Michael Jirousek; Lois E H Smith; George L King
• Keywords: Vascular permeability

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