The Role of Müller Cell-Derived Hypoxia-Inducible Factor (HIF)-1 on Retinal Neovascularization

Abstract

Purpose: : Hypoxia-inducible factor (HIF)-1 is known to play a crucial role in ischemia-induced retinal neovascularization and diabetic retinopathy. The purpose of this study is to determine the role of the Müller cell-derived HIF-1 in retinal neovascularization using Müller cell-specific HIF-1α knockout (KO) mice.

Methods: : The conditional HIF-1α KO mice were generated by mating the Müller cell-specific Cre mice with the floxed HIF-1 mice. Retinal neovascularization was induced by exposure of the mice to 75% oxygen from P7 to P12. The retinal homogenates were used to evaluate the expression of HIF-1 and VEGF at P17. Retinal neovascularization was visualized by fluorescein angiography on flat-mounted retina and quantified by counting pre-retinal vascular cells at P19.

Results: : The wild-type (Wt) mice with OIR showed over-expression of VEGF in the retina and severe pre-retinal neovascularization. In contrast, Muller cell-specific HIF-1α KO attenuated the increases of HIF-1 and VEGF levels in the retina induced by OIR. Consistently, numbers of retinal neovascular tufts and pre-retinal vascular cells were significantly reduced in the conditional HIF -1 KO mice with OIR, compared to Wt mice with OIR.

Conclusions: : The Müller cell-derived HIF-1 plays a key role in ischemia-induced retinal neovascularization, suggesting that HIF-1 in Müller cells is a therapeutic target for the treatment of diabetic retinopathy.

Keywords: Muller cells • hypoxia • retinal neovascularization