Prolonged Blockade of VEGF Receptors Does Not Damage Retinal Photoreceptors or Ganglion Cells

Abstract

Purpose: : A VEGF receptor kinase inhibitor, SU4312, was used to assess possible retinal toxicity induced by antagonism of VEGF signaling.

Methods: : Transgenic mice with sustained expression of VEGF in photoreceptors (rho/VEGF mice) were used to identify a SU4312 dosing regimen that completely suppressed the angiogenic effects of high levels of VEGF in the retina. Wild type mice were given this dosing regimen of SU4312 for up to 12 weeks. Retinal function was assessed by performing serial electroretinograms (ERGs) and retinal structure was assessed by TUNEL and measurement of outer nuclear layer (ONL) thickness. Primary retinal ganglion cell and total retinal cultures were incubated in high concentrations of SU4312 and cell viability was assessed.

Results: : Using rho/VEGF mice, we determined that periocular injection of 3 µg of SU4312 every 5 days completely suppressed subretinal neovascularization indicating effective blockade of VEGF signaling. Wild type mice given periocular injections of 5 µg of SU4312 every 5 days for up to 12 weeks showed normal scotopic and photopic electroretinograms (ERGs), no TUNEL stained cells in the retina, and no reduction in outer nuclear layer thickness. Incubation of cultured ganglion cells or total retinal cultures containing photoreceptors with high doses of SU4312 did not reduce cell viability.

Conclusions: : We recently found that expression of a vascular endothelial growth factor (VEGF) binding protein in the retina for 7 months completely blocked the vascular leakage-promoting effects of VEGF, but did not cause identifiable toxicity to retinal neurons. However, others have reported that much briefer periods of treatment with a VEGF antagonist caused photoreceptor cell death. Our earlier work plus the data presented here suggest that blockade of VEGF signaling in the retina for up to 12 weeks does not damage photoreceptors nor alter ERG function and should reassure patients who are receiving frequent injections of VEGF antagonists for choroidal and retinal vascular diseases.

Keywords: vascular endothelial growth factor • ganglion cells • photoreceptors