Abstract
Vascular endothelial growth factor (VEGF or VEGF-A), a major therapeutic target for blood-retina barrier breakdown (BRB) in diabetic retinopathy (DR), neovascular age-related macular degeneration (AMD), and other and hypoxic retinal diseases, has been shown to act as a direct functional regulator for peripheral and central nervous system (CNS) neurons. To investigate the direct effect of VEGF on photoreceptor function in DR and hypoxic retinal diseases, we examined and compared the effect of recombinant (rVEGF) on retinal function with electroretinography (ERG) in Akita spontaneous diabetic mice and wild-type (WT) mice kept under normal environment and hypoxia (8 percent oxygen for 5 days). Retinal function was measured with ERG in dark-adapted mice immediately after rVEGF intravitreally delivery under long-wavelength illumination. While the rVEGF caused a significant reduction of scotopic ERG a-wave and b-wave amplitudes and photopic ERG b-wave amplitudes in a dose-dependent manner in WT mice kept under normal conditions, the effect of rVEGF on the alteration of ERG amplitudes was diminished in age-matched Akita diabetic and hypoxic mice in which retinal VEGF levels are upregulated. Our results suggest that VEGF is a most likely direct functional regulator of photoreceptors. Our data strongly support that VEGF upregulation is a likely cause of the reduced photoreceptor function in DR and hypoxic retinal disorders. As VEGF is a major therapeutic target for BRB breakdown in DR, AMD, and other hypoxic retinal BRB diseases, our work provides the mechanistic insights for the therapeutic effects on visual acuity and for the care of anti-VEGF drug treated patients. Disclosure Y.Le: None. M.Zhu: None. Funding National Institutes of Health (R01EY26970, P30EY021725, P30GM122744); Oklahoma Center for the Advancement of Science and Technology (HR20-065)
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