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Faizah N Bhatti, Madeline Edwards, Geneveive Ball; Surfactant Protein A Impacts both Vascular Regression and Neoproliferation in a Mouse Model of Oxygen Induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5377.
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We have previously shown that surfactant protein A (SP-A) is expressed in the mouse retina in Müller cells and in proximity to retinal vasculature and that it is up regulated by toll-like receptor 2 and 4 stimulation. We also showed that SP-A modulates human retinal endothelial cell function in vitro. In this study, we hypothesized that SP-A signaling alters vascular development in the preterm neonate impacting retinopathy of prematurity (ROP). We tested this hypothesis in an in vivo oxygen-induced retinopathy (OIR) model with Wild Type (WT) and SP-A null mice.
To study vaso-obliteration (VO), WT and SP-A null mice were exposed to 75% hyperoxia from P5 to P10. The animals were sacrificed on P10 and retinas flat mounted after immunostaining with cd31. In a separate experiment, to study Neovascularization (NV), WT and SP-A null litters were kept in room air until P7 and then 75% hyperoxia from P7 to P12. The animals were sacrificed on P17 and flat mounted retinas analyzed for total area, VO and NV. VO and NV areas were expressed as percentage of total retinal area and compared using Student's t-test. p<0.05 was considered significant. Vascular endothelial growth factor (VEGF-A) protein content was also analyzed in retina homogenates by western blotting.
In mice exposed to 75% O2 from P5 to P10, WT mice had greater VO area compared to SP-A null (WT 40% vs SP-A null 32% p=0.006). In the second experiment with the complete OIR model, SP-A null mice had greater VO area compared to WT (30.1% vs 23.6% p=0.13), but had decreased NV area (14.4% vs 30% p=0.001). VEGF-A protein was increased by 2 fold in SP-A null mice compared to WT mice with OIR.
Although SP-A null mice exposed to hyperoxia alone had decreased VO, they had a slight increase in VO when placed in hyperoxia at P7-P12. The decrease in NV in SP-A null mice suggests that the absence of SP-A may lead to a decrease in inflammatory cytokines, impacting blood vessel growth in the second phase of ROP. Even though SP-A null mice had an increase in VEGF levels, cytokine signaling may be impacting blood vessel growth by pathways independent of hypoxia induced factors. Thus SP-A may be protective in maintaining vascular growth in the first phase of ROP, but overexpression (due to inflammation) may impact the second phase of vascular neo-proliferation.
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