Effect of Increased Vascular Endothelial Growth Factor on Inner Retinal Oxygen Delivery and Metabolism in Rats

Abstract

Purpose: Increased vascular endothelial growth factor (VEGF) promotes angiogenesis and vascular permeability and plays an important role in development of retinal pathologies. Accordingly, anti-VEGF agents are an optimal treatment for neovascular aged-related macular degeneration and diabetic retinopathy. The purpose of this study is to report the effect of increased VEGF on inner retinal oxygen delivery (DO_{2_IR}) and oxygen metabolism (MO_{2_IR}) in rats.

Methods: Retinal vascular oxygen tension (PO₂) and blood flow were measured in both eyes of 6 rats under systemic normoxia, one day following intravitreal injection of VEGF in one eye (study) and balanced salt solution in the fellow eye (control). Retinal vascular PO₂ was measured in major retinal arteries (PO_2A) and veins (PO_2V) by phosphorescence lifetime imaging. Arterial (O_2A) and venous (O_2V) oxygen contents were calculated from these measurements using the hemoglobin dissociation curve. Venous blood velocity (V) was measured by fluorescent microsphere imaging and venous diameter (D) was obtained by red-free retinal imaging. DO_{2_IR} was determined from the product of total retinal blood flow (F = πD²V/4) and O_2A, while MO_{2_IR} was calculated from the product of F and arteriovenous oxygen content difference (O_2A - O_2V). Retinal oxygenation parameters were compared between study and control eyes using paired Students t-test.

Results: Mean PO_2V and O_2V were significantly higher in study eyes compared to control eyes (p ≤ 0.04), while both mean PO_2A and O_2A were not significantly different between study and control eyes (p ≥ 0.67). Mean D was significantly higher in study eyes (p = 0.01) and mean V was similar between study and control eyes (p = 0.61). Consequently, F was significantly higher in study eyes compared to control eyes (p = 0.02). Mean DO_{2_IR} in study eyes (1531 ± 651 nLO₂ /min, N = 6) was significantly higher than in control eyes (1026 ± 368 nLO₂/min, N = 6) (p = 0.03), while mean MO_{2_IR} was not significantly different between study eyes (555 ± 179 nLO₂/min) and control eyes (499 ± 129 nLO₂/min) (p = 0.36).

Conclusions: Administration of VEGF resulted in increased F and DO_{2_IR} due to vasodilation, but did not affect MO_{2_IR}. These findings may have implications in the pathophysiology and treatment of retinal diseases associated with hypoxia and increased VEGF production.

Keywords: 551 imaging/image analysis: non-clinical • 592 metabolism • 748 vascular endothelial growth factor