Neuronal Socs3 deficiency promotes pathologic retinal angiogenesis

Abstract

Purpose: Although the hallmark of retinopathy of prematurity (ROP) is abnormal retinal vasculature, increasing evidence supports a critical role for the neural retina in the ROP disease process. The purpose of the present study was to identify a novel mechanism involved in neurovascular interaction and the pathophysiology of retinopathy by showing that neuronal suppressor of cytokine signaling-3 (Socs3) deficiency promotes pathologic retinal angiogenesis in retinopathy.

Methods: Since systemic Socs3 knockout (KO) mice are embryonic lethal, we generated conditional KO of Socs3 in retinal neurons using a Cre/loxP site-specific DNA recombination fate mapping strategy. Socs3 is deleted in neuronal system by crossing mice expressing the Cre recombinase transgene under the control of the nestin (Nes) promoter and enhancer with mice carrying Socs3/loxP. Developmental and pathologic retinal angiogenesis in these mice was studied using a mouse model of oxygen-induced retinopathy (OIR), in which neonatal pups are exposed to 75% oxygen from postnatal day (P) 7 to 12.

Results: Conditional Nes-Cre-Socs3ko mice subjected to OIR had significantly increased levels of pathologic retinal neovascularization compared with littermate controls (Socs3flox/flox) at P17 (Nes-Cre-Socs3ko, 11.65%±0.65%, n=27; Socs3flox/flox, 8.30%±0.57%, n=10; P=0.002). The vaso-obliterated retinal area was significantly reduced (p=0.004) in Nes-Cre-Socs3ko (13.65%±1%, n=27) compared with Socs3flox/flox mice (16.8%±0.49%, n=10). In contrast, developmental retinal vascularization is not affected by Socs3 neuronal deletion.

Conclusions: These results indicate that neuronal Socs3 suppresses retinal angiogenesis under pathologic conditions (with stress) but is dispensable in physiologic vascular development. These results identify neuronal Socs3 as an inhibitor of pathologic angiogenesis and a potential novel therapeutic target to treat retinopathy.

Keywords: 490 cytokines/chemokines • 700 retinal neovascularization • 706 retinopathy of prematurity