Galectin-1 expression imprints a neurovascular phenotype in proliferative retinopathies and delineates responses to anti-VEGF.

Magali E Ridano,Ana L Gramajo,Gabriel A Rabinovich,Valeria E Lorenc,Juan C Stupirski,María C Paz,Diego O Croci,José D Luna,Paula V Subirada,María C Sánchez

doi:10.18632/oncotarget.17129

Abstract

Neovascular retinopathies are leading causes of irreversible blindness. Although vascular endothelial growth factor (VEGF) inhibitors have been established as the mainstay of current treatment, clinical management of these diseases is still limited. As retinal impairment involves abnormal neovascularization and neuronal degeneration, we evaluated here the involvement of galectin-1 in vascular and non-vascular alterations associated with retinopathies, using the oxygen-induced retinopathy (OIR) model. Postnatal day 17 OIR mouse retinas showed the highest neovascular profile and exhibited neuro-glial injury as well as retinal functional loss, which persisted until P26 OIR. Concomitant to VEGF up-regulation, galectin-1 was highly expressed in P17 OIR retinas and it was mainly localized in neovascular tufts. In addition, OIR induced remodelling of cell surface glycophenotype leading to exposure of galectin-1-specific glycan epitopes. Whereas VEGF returned to baseline levels at P26, increased galectin-1 expression persisted until this time period. Remarkably, although anti-VEGF treatment in P17 OIR improved retinal vascularization, neither galectin-1 expression nor non-vascular and functional alterations were attenuated. However, this functional defect was partially prevented in galectin-1-deficient (Lgals1−/−) OIR mice, suggesting the importance of targeting both VEGF and galectin-1 as non-redundant independent pathways. Supporting the clinical relevance of these findings, we found increased levels of galectin-1 in aqueous humor from patients with proliferative diabetic retinopathy and neovascular glaucoma. Thus, using an OIR model and human samples, we identified a role for galectin-1 accompanying vascular and non-vascular retinal alterations in neovascular retinopathies.

Highlights

Proliferative neovascular retinopathies are major leading causes of blindness in industrialized countries [1]
terminal deoxynucleotidyltransferase biotin dUTP nick end labeling (TUNEL)-positive nuclei were detected in the ganglion cell layer (GCL), within the inner nuclear layer (INL; mainly neurons such as bipolar and amacrine cells), as well as in outer nuclear layer (ONL; photoreceptors) in oxygen-induced retinopathy (OIR) retinas (Figure 1C)
It is well known that Müller glial cells and neurons are compromised in experimental neovascular www.impactjournals.com/oncotarget retinopathies, such as in the OIR mouse model [37,38,39], and that gliosis may contribute to NV and neuronal cell death [40]

Summary

Introduction

Proliferative neovascular retinopathies are major leading causes of blindness in industrialized countries [1]. Vision loss in retinopathy of prematurity and proliferative diabetic retinopathy are caused by several growth factors [2, 3], including vascular endothelial growth factor-A (VEGF-A), the most potent cytokine that mediates ischemia-induced retinal neovascularization (NV) in ocular pathologies [4, 5]. VEGF-A exerts its effects via activation of various signaling events, including tyrosine phosphorylation of its receptors VEGFR1 (Flt1), VEGFR2 (KDR/Flk-1), and VEGFR3 (Flt-4) and their downstream effectors on endothelial cells (ECs) [6]. Accumulating evidences, stemming from experimental models and clinical studies have provided insights into the mechanisms of vascular injury leading to pathological vitreoretinal NV, leading to discovery and implementation of ocular anti-VEGF therapies [7]. The clinical benefit conferred by these therapies is variable and the results have not always been successful in preserving retinal function [2]

Methods

Results

Conclusion