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

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.

Galectin‐1 promotes choroidal neovascularization and subretinal fibrosis mediatedviaepithelialmesenchymal transition

“…Supporting these findings, binding of galectin-1 to VEGFR2 has recently been shown to mediate its downstream signal transduction (e.g., phosphorylation of ERK1/2) in human umbilical vein and retinal microvascular endothelial cells, thereby promoting angiogenesis in cancer and proliferative diabetic retinopathy (16,17). In the mouse model of oxygeninduced retinopathy as well, galectin-1 has been shown to contribute to ischemia-induced retinal neovascularization (41)(42)(43), in which VEGFA-mediated inflammation is necessary for pathologic, but not physiologic, vessel growth (44). CNV is also based on the inflammatory pathogenesis that depends on endothelial production of CCL2/MCP1 (32) and ICAM1 (33), both of which proved to be regulated under VEGFR2 (29-31) and ERK1/2 (34)(35)(36) and to be responsible for the recruitment of proangiogenic macrophages (44,45).…”

VEGF‐Trap is a potent modulator of vasoregenerative responses and protects dopaminergic amacrine network integrity in degenerative ischemic neovascular retinopathy

“…The multifactoriality of ocular vasculopathies and adaptive resistance because of compensatory up‐regulation of factors other than VEGF‐A might represent a significant hurdle for VEGF‐A inhibitors that ultimately renders tissues non‐responsive to these agents. Such phenomenon is well‐described in tumor biology (Croci and Rabinovich ; Li et al ) and, in the context of neovascular retinopathies, might result in the persistence of visual deficits (Rakic et al ; Shih et al ; Cheung et al ; Hammes et al ; Gupta et al ; Semeraro et al ; Roy et al ; Ridano et al ) or lead to substantial visual decline in initial responders even several years after anti‐VEGF‐A treatment (Rofagha et al ). Interestingly, conventional anti‐VEGF‐A agents fail to restore visual function also in OIR mice, presumably because of compensatory up‐regulation of alternative angiogenic factors (Ridano et al ).…”

“…Such phenomenon is well‐described in tumor biology (Croci and Rabinovich ; Li et al ) and, in the context of neovascular retinopathies, might result in the persistence of visual deficits (Rakic et al ; Shih et al ; Cheung et al ; Hammes et al ; Gupta et al ; Semeraro et al ; Roy et al ; Ridano et al ) or lead to substantial visual decline in initial responders even several years after anti‐VEGF‐A treatment (Rofagha et al ). Interestingly, conventional anti‐VEGF‐A agents fail to restore visual function also in OIR mice, presumably because of compensatory up‐regulation of alternative angiogenic factors (Ridano et al ). Thus, the use of broad‐spectrum inhibitory agents is warranted in the context of neovascular retinopathies, including diabetic retinopathy (Van Huang et al ; de Veire et al ; Ridano et al ).…”

“…The oxygen‐induced retinopathy (OIR) mouse model is the most widely used animal model to study ischemic neovascular retinopathies including retinopathy of prematurity and late neovascular proliferative diabetic retinopathy (Smith et al ; Stahl et al ). As in human ischemic retinopathy patients, retinal function is markedly impaired in OIR mice (Stahl et al ; Dorfman et al ; Vessey et al ; Ridano et al ; Matsuda et al ). Moreover these mice also exhibit reduced numbers of dopaminergic amacrine cells (Spix et al ) and delayed intermediate vascular plexus formation (Ritter et al ; Spix et al ).…”

“…Interestingly, conventional anti‐VEGF‐A agents fail to restore visual function also in OIR mice, presumably because of compensatory up‐regulation of alternative angiogenic factors (Ridano et al ). Thus, the use of broad‐spectrum inhibitory agents is warranted in the context of neovascular retinopathies, including diabetic retinopathy (Van Huang et al ; de Veire et al ; Ridano et al ).…”