ABSTRACT
Purpose/Aim
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.
Materials and methods
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 Stc-1−/- 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.
Results
STC-1 was significantly upregulated in a rat model of OIR compared to room air controls at the gene (P < .05) and protein (P < .001) level. Stc-1−/- OIR mice showed significantly worse ROP compared to wild-type mice as assessed by avascular (20.2 ± 2.4% vs 15.2 ± 2.5%; P = .02) and neovascular area (14.3 ± 2.7% vs 8.8 ± 3.7%; P < .05). Transcript levels of vascular endothelial growth factor-A were significantly higher in Stc-1−/- OIR mice compared to wild-type controls (P = .03). STC-1 reduced VEGF production in iPS-RPE cells (P = .01).
Conclusions
STC-1 plays a role in the OIR stress response and development of pathologic vascular features in rodent OIR models by regulating VEGF levels.
Contributions of the authors
Lauren A. Dalvin, generation, and analysis of experimental data, editing of manuscript.
Mary Elizabeth Hartnett, planning of studies, generation and analysis of experimental data, editing of manuscript.
Colin A. Bretz, generation of experimental data, editing of manuscript.
Cheryl R. Hann, generation of experimental data.
Ricky Z. Cui, generation of experimental data.
Alan D. Marmorstein, planning of experiments.
David Sheikh-Hamad, provision of study materials, editing of manuscript.
Michael P. Fautsch, planning of studies, generation and analysis of experimental data, editing of manuscript.
Gavin W. Roddy, planning of studies, generation and analysis of experimental data, writing and editing of manuscript.
Supplementary material
Supplemental data for this article can be accessed here.