Abstract
Proliferative retinopathies produces an irreversible type of blindness affecting working age and pediatric population of industrialized countries. Despite the good results of anti-VEGF therapy, intraocular and systemic complications are often associated after its intravitreal use, hence novel therapeutic approaches are needed. The aim of the present study is to test the effect of the AS1411, an antiangiogenic nucleolin-binding aptamer, using in vivo, ex vivo and in vitro models of angiogenesis and propose a mechanistic insight. Our results showed that AS1411 significantly inhibited retinal neovascularization in the oxygen induced retinopathy (OIR) in vivo model, as well as inhibited branch formation in the rat aortic ex vivo assay, and, significantly reduced proliferation, cell migration and tube formation in the HUVEC in vitro model. Importantly, phosphorylated NCL protein was significantly abolished in HUVEC in the presence of AS1411 without affecting NFκB phosphorylation and -21 and 221-angiomiRs, suggesting that the antiangiogenic properties of this molecule are partially mediated by a down regulation in NCL phosphorylation. In sum, this new research further supports the NCL role in the molecular etiology of pathological angiogenesis and identifies AS1411 as a novel anti-angiogenic treatment.
Highlights
Pathological angiogenesis in the retina resulting from proliferative diabetic retinopathy (PDR), wet age-related macular degeneration (AMD), retinal artery occlusion, retinal vein occlusion and retinopathy of prematurity (ROP) have in common the production of proangiogenic growth factors [1]
(2) Hyperoxia condition developed pathological angiogenesis located at the superficial retina with a disorganized distribution
OUIsRinign vOiIvRo model and rat aortic ring ex vivo model, we showed that AS1411 induced an inhibition in neoangiogenesis as ranibizumab did, which is a Vascular endothelial growth factor (VEGF)-inhibitor clinically approved for human retinopathies
Summary
Pathological angiogenesis in the retina resulting from proliferative diabetic retinopathy (PDR), wet age-related macular degeneration (AMD), retinal artery occlusion, retinal vein occlusion and retinopathy of prematurity (ROP) have in common the production of proangiogenic growth factors [1]. Since the pathophysiology of the aforementioned diseases involves a disruption of the blood-retinal barrier (BRB) and pathological angiogenesis, the final consequence is irreversible blindness affecting working age and pediatric population of industrialized countries. This abnormal and disproportionate hyper-vascularization is a compensatory mechanism to overcome the metabolic equilibrium to the hypoxic retina due to microvessel degeneration [2]. Intravitreal humanized monoclonal antibodies (huMAb) against VEGF, such as ranibizumab and aflibercept, have being used for PRD, AMD, ROP, macular edema after retinal vein occlusion, vitreous hemorrhage, neovascular glaucoma, among other retinovascular diseases [6]. Systemic VEGF inhibition is likely to cause cardiovascular complications [31] and renal dysfunction [32]
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