Abstract
Mechanistic understanding and defining novel therapeutic targets of diabetic retinopathy and age-related macular degeneration (AMD) have been hampered by a lack of appropriate adult animal models. Here we describe a simple and highly reproducible adult fli-EGFP transgenic zebrafish model to study retinal angiogenesis. The retinal vasculature in the adult zebrafish is highly organized and hypoxia-induced neovascularization occurs in a predictable area of capillary plexuses. New retinal vessels and vascular sprouts can be accurately measured and quantified. Orally active anti-VEGF agents including sunitinib and ZM323881 effectively block hypoxia-induced retinal neovascularization. Intriguingly, blockage of the Notch signaling pathway by the inhibitor DAPT under hypoxia, results in a high density of arterial sprouting in all optical arteries. The Notch suppression-induced arterial sprouting is dependent on tissue hypoxia. However, in the presence of DAPT substantial endothelial tip cell formation was detected only in optic capillary plexuses under normoxia. These findings suggest that hypoxia shifts the vascular targets of Notch inhibitors. Our findings for the first time show a clinically relevant retinal angiogenesis model in adult zebrafish, which might serve as a platform for studying mechanisms of retinal angiogenesis, for defining novel therapeutic targets, and for screening of novel antiangiogenic drugs.
Highlights
Pathological angiogenesis in the retina is the leading cause of human blindness resulting from diabetic retinopathy, age-related macular degeneration (AMD), and retinopathy of prematurity (ROP)
4–9 main vessel branches derived from the optic artery were distributed in each optic disc and they were further divided 2–5 times before anastomosing with circumferential vein capillaries (CVC)
Intercapillary distances and retinal neovascularization areas were normalized to the levels of retinas exposed to normoxia (Fig. 4I and J). These findings indicate that the hypoxia-triggered VEGF signaling pathway is the primary angiogenic driving force for retinal neovascularization in adult zebrafish
Summary
Pathological angiogenesis in the retina is the leading cause of human blindness resulting from diabetic retinopathy, age-related macular degeneration (AMD), and retinopathy of prematurity (ROP). Despite of significant advances in medical care, diabetic retinopathy, AMD and ROP continue to remain the leading causes of vision impairment and blindness in adults and infants respectively [1,2,3,4]. These common ocular disorders are characterized by overgrowth of disorganized, leaky and physiologically non-functional retinal vessels, which lead to vision impairment and blindness [1,4]. The infant retina is relatively hypoxic leading to pathological angiogenesis This model does not accurately reproduce human ROP
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