Inhibition of Soluble Vascular Endothelial Growth Factor 2: A Model for Pathogenic Lymphangiogenesis in the Eye

Abstract

Purpose: : We recently described a novel splice variant of vascular endothelial growth factor receptor 2 (sVEGFR-2) that specifically inhibits lymphatic vessel growth induced by VEGF-C (Albuquerque et al. Nature Medicine 2009) and is essential for an alymphatic cornea. We investigated the potential function of sVEGFR-2 in maintaining the alymphatic nature of the mouse retina.

Methods: : We studied sVEGFR-2 and VEGF-C expression in the posterior segment of the mouse eye by immunohistochemistry. Mouse blood endothelial cells expressing sVEGFR-2 were used to identify small interfering RNAs (siRNAs) capable of target knockdown, as assessed by real-time RT-PCR. Cell permeating siRNAs targeting sVEGFR-2 were injected into the vitreous humor of mice, and intraocular vasculature was defined by CD31/LYVE-1 immunostaining.

Results: : Mouse optic nerve and retina expressed sVEGFR-2 and VEGF-C. Two siRNAs that knocked down sVEGFR-2 mRNA in cell culture by 70-90% were identified. Inhibition of sVEGFR-2 modulated the spatial distribution of intraocular vasculature.

Conclusions: : The endogenous lymphangiogenesis inhibitor sVEGFR-2, which is required for creation and maintanence of an alymphatic cornea, also may be responsible for the alymphatic nature of the retina despite the presence of VEGF-C.

Keywords: vascular endothelial growth factor • retinal development • optic nerve