PURPOSE. Stem cell factor (SCF) has recently demonstrated activity as a novel endothelial permeability factor that contributes to the development of diabetes-induced hyperpermeable retinal vasculature. This study investigated the therapeutic potential of masitinib, a pharmacologic inhibitor of the SCF receptor cKit, for prevention of diabetes-induced breakdown of blood retinal barrier (BRB). METHODS. Permeability assays were performed with human retinal microvascular endothelial cells (HRMECs) and murine retinal vasculature. Localization of vascular endothelial (VE)- cadherin and activation of SCF signaling pathway was determined by immunofluorescence and Western blotting assays. Mice and rats with streptozotocin (STZ)-induced diabetes were used to investigate the role of cKit and masitinib in diabetes-induced retinal vascular hyperpermeability. RESULTS. Masitinib substantially blocked SCF-induced phosphorylation of cKit in HRMECs. In vitro and in vivo vascular permeability assays showed that masitinib significantly inhibited SCF-induced endothelial hyperpermeability and junctional loss of VE-cadherin. Streptozoto- cin-induced diabetes was induced in cKit-mutant mice with low cKit expression in their endothelial cells. Although diabetic wild-type mice exhibited enhanced retinal vascular leakage, diabetic cKit-mutant mice showed no increase in retinal vascular leakage or alteration in the distribution of VE-cadherin; this indicates the crucial role of cKit in diabetes-induced breakdown of BRB. Moreover, in vivo prevention experiments showed that an intravitreal injection of masitinib substantially inhibited the development of hyperpermeable retinal vasculature. CONCLUSIONS. These results provide the first demonstration that cKit inhibitors, such as masitinib, might be promising therapeutics for prevention of diabetes-induced breakdown of the BRB.
All Science Journal Classification (ASJC) codes
- Sensory Systems
- Cellular and Molecular Neuroscience