Role of the Retinal Müller Cells in Diabetic Retinopathy

Abstract

Purpose:: Retinal neovascularization and retinal vascular leakage are the common pathogenic changes and major causes of vision loss in diabetic patients. Over-expression of vascular endothelial growth factor (VEGF or VEGF-A) in diabetic retina plays a pivotal role in these pathogenic changes. It has been suggested that the retinal Müller cell is the major source of VEGF in diabetic retina and thus, the major player in diabetic retinopathy. However, the significance of Müller cell-produced VEGF in diabetic retinopathy has not been well investigated. To reveal the role of the retinal Müller cells in diabetic retinopathy, we disrupted Müller cell-produced VEGF in mice using tetracycline-inducible system and Cre/lox technology, and investigated the effect of VEGF disruption on retinal neovascularization and vascular leakage.

Methods:: Inducible Müller cell-specific VEGF knockout mice were generated by mating the floxed VEGF mice with the tetracycline-inducible Müller cell-specific Cre mice developed in our laboratories. The conditional VEGF knockout mice were subjected to an oxygen inducible retinopathy (OIR) model. The VEGF expression, retinal neovascularization, and vascular leakage in the OIR-treated conditional VEGF knockout mice were analyzed with immunohistochemistry, fluorescein angiography, and quantification of neovascular nuclei.

Results:: VEGF expression was reduced significantly in the conditional VEGF knockout mice. Inducible disruption of VEGF in the retinal Müller cells caused reduced neovascularization and vascular leakage in the OIR model.

Conclusions:: Our study demonstrates unequivocally that the retinal Müller cell-produced VEGF plays an important role in retinal neovascularization. Although the function of VEGF in retinal neovascularization is widely acknowledged, the role of retinal Müller cells in neovascularization has not been well investigated. Our study provides a genetic system to study the cellular mechanisms that regulate retinal neovascularization. These studies are in progress.

Keywords: diabetic retinopathy • Muller cells • neovascularization