MOLECULAR MECHANISMS OF ANGIOGENESIS-RELATED OCULAR DISEASES IN PRECLINICAL MODELS

Neovascularization in the eye contributes to visual loss in several ocular diseases, including proliferative diabetic retinopathy (PDR), neovascular glaucoma (NVG) and retinopathy of prematurity (ROP). In these diseases, the neovascular mechanisms originate from the retina, but some advanced stages of PDR or nG can lead to the development of rubeosis iridis (RI), a clinical manifestation characterized by iris angiogenesis. Vascular endothelial growth factors (VEGFs) and their receptor (VEGFRs) are the key promoters of angiogenesis, playing a crucial role in both physiological and pathological angiogenesis. For this reason, anti-VEGF therapies have represented a great step forward in the treatment of ocular neovascular diseases, but the effects can be somewhat limited. In addition, beyond the vascular alterations, degenerative changes might occur in the neuroretina, including inflammation and neurodegeneration, which further compromise visual function in people affected by ocular diseases. Consequently, a pharmacologic strategy aimed at inhibiting several pathways might be a more suitable therapeutic approach. A first suitable target may be represented by the pathway triggered by the urokinase plasminogen activator (uPA) and its receptor (uPAR), which play a pivotal role in extracellular matrix remodeling during angiogenesis, where uPAR, a glycosylphosphatidylinositol-anchored protein, regulates cell migration and proliferation through the assembly with transmembrane receptors. An additional pathway that may represent an interesting target is autophagy, as an expanding body of literature suggests that mechanisms of autophagy are involved in neurodegeneration in ocular disease. Autophagy is an essential process in maintaining the normal cellular homeostasis and energy balance. In retinal diseases, autophagy contributes to retinal cells protecting themselves against harmful stress stimuli; however, dysregulated autophagy may result in retinal deterioration. Here, we investigate the effects of the uPAR antagonist—UPARANT—on the angiogenic and inflammatory processes, in a context of hypoxia-induced angiogenesis, using a novel ex vivo human iris angiogenesis assay and, an in vivo mouse model of RI-associated with proliferative retinopathy (PR). A rat model of oxygen-induced retinopathy (OIR), an acknowledged model of ROP, was used to evaluate neuroretinal changes in the expression of key mediators of autophagy, induced by disease. First, we investigated the autophagic profile in newborn rats and, subsequently determined a correlation between autophagy and mechanisms of cell death in the OIR rat retina. In addition, an inhibitor of autophagy was valuated to analyze the possible effects of in mitigating autophagy-associated cell death and retinal function in the OIR rat model.