VEGF-A Plays a Major Retinal Neuroprotective Role in the Adaptive Response to Ischemic Injury

Abstract

Purpose:: As vascular endothelial growth factor-A (VEGF-A) has recently been recognized to play an important neuroprotective role within the central nervous system, we investigated the effects of both exogenous and endogenous VEGF-A on neuronal protection within the retina using models of ischemia reperfusion injury.

Methods:: These experiments used two models 1) an ischemia/reperfusion model in which transient retinal ischemia was induced in rats by inserting a ligature around the optic nerve for 60 minutes; VEGF-A was injected intravitreously (IVT) following release of the ligature; 2) an ischemic preconditioning model in which a 5-minute episode of ischemia was followed by IVT VEGFR-1/Fc protein or vehicle; 24-hours later a 60-minute period of ischemia was induced. Apoptosis of retinal neurons was assessed by TUNEL staining at various timepoints after injury; VEGFR-2 and VEGF-A levels were quantified. In other experiments, rat eyes were harvested 14 days after ischemia/reperfusion injury to determine the thickness of various retinal neural layers. Finally, retinal explants from 2-day old rats were cultured in the presence/absence of VEGF120 and apoptotic cells were quantified after 24 hours for TUNEL staining.

Results:: IVT administration of VEGF-A resulted in a dose-dependent reduction in the apoptosis of retinal neurons after ischemia/reperfusion injury. Ischemic preconditioning one day prior to ischemia/reperfusion injury increased VEGF-A levels and substantially decreased the number of apoptotic retinal cells. This protective effect was reversed after VEGF-A inhibition, confirming a role for VEGF-A in the adaptive response to retinal ischemia. Both VEGF-A-induced increased volumetric blood flow to the retina and direct neuroprotective activity contributed to these effects.

Conclusions:: These results identify VEGF-A as a component of the endogenous adaptive response for protecting neural cells during retinal ischemia.

Keywords: neuroprotection • retina • ischemia