Stanniocalcin-1 is a Modifier of Oxygen-Induced Retinopathy Severity

Abnormal activation of signaling pathways related to angiogenesis, inflammation, and oxidative stress has been implicated in the pathophysiology of retinopathy of prematurity (ROP), a leading cause of blindness in pre-term infants. Therapies for ROP include laser and anti-vascular endothelial growth factor agents. However, these therapies have side effects, and even with adequate treatment, visual acuity can be impaired. Novel therapeutic options are needed. Stanniocalcin-1 (STC-1) is a neuroprotective protein with anti-inflammatory and anti-oxidative stress properties. Rodent models of oxygen-induced retinopathy (OIR) were selected to determine whether STC-1 plays a role in the development of OIR. STC-1 gene and protein expression was first evaluated in the Sprague Dawley rat OIR model that is most similar to human ROP. OIR was then induced in wild-type and <i>Stc-1^−/-</i> mice. Retinas were isolated and evaluated for avascular and neovascular area on retinal flat mounts. Quantification of gene expression by quantitative real-time PCR was performed. VEGF was assayed by ELISA in media obtained from induced pluripotent stem-cell-derived retinal pigment epithelial (iPS-RPE) cells following treatment with recombinant STC-1. STC-1 was significantly upregulated in a rat model of OIR compared to room air controls at the gene (<i>P</i> &lt; .05) and protein (<i>P</i> &lt; .001) level. <i>Stc-1^−/-</i> OIR mice showed significantly worse ROP compared to wild-type mice as assessed by avascular (20.2 ± 2.4% vs 15.2 ± 2.5%; <i>P</i> = .02) and neovascular area (14.3 ± 2.7% vs 8.8 ± 3.7%; <i>P</i> &lt; .05). Transcript levels of vascular endothelial growth factor-A were significantly higher in <i>Stc-1^−/-</i> OIR mice compared to wild-type controls (<i>P</i> = .03). STC-1 reduced VEGF production in iPS-RPE cells (<i>P</i> = .01). STC-1 plays a role in the OIR stress response and development of pathologic vascular features in rodent OIR models by regulating VEGF levels.