ROLE OF NEURONAL SPERMINE OXIDASE IN VASCULAR DAMAGE IN A MODEL OF ISCHEMIC RETINOPATHY

Abstract

Retinal vascular injury is a major cause of vision impairment in ischemic retinopathies such as diabetic retinopathy and retinopathy of prematurity (ROP). Current treatments for ischemic retinopathies target the late stage of the disease and have long-term side effects. Therefore, there is a great need to identify novel mechanisms and therapeutic approaches. Previous studies from our laboratory have shown the critical role of spermine oxidase (SMOX) in retinal neurovascular damages. Utilizing the oxygen-induced retinopathy (OIR) mouse model of ROP, the current study was undertaken to investigate the impact of neuronal SMOX in mediating retinal vascular injury. Newborn mice (WT control, SMOX Tg, or WT treated with MDL 72527/saline) along with their mother were maintained in 70% oxygen from postnatal day (P) 7 to 12 followed by normoxia until P17. Animals were sacrificed at P17 and eyes were processed for different experiments. Our data demonstrated that retinal vascular development was normal in the SMOX Tg retina, and MDL 72527 treatment had no deleterious effect on WT retinas. Staining of retinal flat-mounts with Isolectin B4 showed that SMOX overexpression significantly increased OIR induced avascular area and pathological neovascular tufts in SMOX Tg retinas compared to WT-OIR retinas. Treatment with SMOX inhibitor, MDL 72527, significantly reduced these pathological changes. Furthermore, Glial fibrillary acidic protein (GFAP) immunostaining of retinal cryostat sections showed elevated glial activation in SMOX Tg-OIR retinas compared to WT-OIR retinas. Western blot analysis of retinal lysates performed on OIR groups treated with MDL 72527/vehicle demonstrated increased levels of acrolein conjugates compared to normoxia control groups. Considering the urgent need to identify new therapeutic modalities for retinal neovascular diseases, our data suggest that blockade of SMOX signaling can be a potential therapeutic target to limit the progression of ischemic retinopathies.