Abstract
Vascular endothelial growth factor (VEGF) is a major therapeutic target for blood–retina barrier (BRB) breakdown in diabetic retinopathy (DR), age-related macular degeneration (AMD), and other hypoxic retinal vascular disorders. To determine whether VEGF is a direct regulator of retinal neuronal function and its potential role in altering vision during the progression of DR, we examined the immediate impact of recombinant VEGF (rVEGF) on photoreceptor function with electroretinography in C57BL6 background wild-type (WT) and Akita spontaneous diabetic mice. Shortly after intravitreal injections, 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 dark-adapted 1.5-mo-old WT mice. Compared with WT controls, 5-mo-old Akita spontaneous diabetic mice demonstrated a significant reduction in scotopic ERG a-wave and b-wave amplitudes and photopic ERG b-wave amplitudes. However, the effect of rVEGF altered photoreceptor function in WT controls was diminished in 5-mo-old Akita spontaneous diabetic mice. In conclusion, our results suggest that VEGF is a direct functional regulator of photoreceptors and VEGF up-regulation in DR is a contributing factor to diabetes-induced alteration of photoreceptor function. This information is critical to the understanding of the therapeutic effect and to the care of anti-VEGF drug-treated patients for BRB breakdown in DR, AMD, and other hypoxic retinal vascular disorders.
Highlights
To determine if Vascular endothelial growth factor (VEGF) plays a direct role in regulating photoreceptor function, we developed a procedure to evaluate the immediate effect of recombinant VEGF (rVEGF) on retinal neuronal function with
To determine if VEGF-A or VEGF played a directly role in regulating photoreceptor function, we intravitreally injected human rVEGF to overnight dark-adopted C57BL6 background mice (1.5-mo-old) under long-wavelength illumination and recorded ERG
Did not appear to alter the time to reach the trough or peak for both scotopic ERG a-wave and b-wave, rVEGF-injected animals demonstrated a dose-dependent (0.1, 0.3, or 0.5 μg rVEGF/eye) reduction of both scotopic ERG a-wave and b-wave amplitudes (Figure 1), suggesting that rVEGF was capable of downregulating rod photoreceptor function immediately after it diffused to photoreceptors and retinal neurons
Summary
The viability of retinal neurons is reduced during early diabetes in streptozotocin-injected rodent models, as demonstrated by increasing neuronal apoptosis and retinal thinning, including the thinning of the inner nuclear layer (INL) and outer nuclear layer (ONL) [1,5]. Elevated VEGF levels could upregulate its downstream signaling cascade and play an important role in altering neuronal function in the retina during the progression of diabetes, such as impairing visual function through alteration of visual cycle and phototransduction machinery in DR [18] This assumption is supported by well-established observations that both VEGF receptor-1 (VEGFR1) and VEGFR2 are present in the neural retina, including photoreceptors [19,20], in which the role of VEGF as a trophic factor for retinal neurons under stress conditions has been identified [7,20,21,22,23]. This article summarizes our work in revealing the role of VEGF in photoreceptor function using wildtype (WT) or Akita spontaneous diabetic mice [24]
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