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Neurovascular Injury After Retinal Ischemia Reperfusion Insult: Contrasting Roles Of Arginase Enzyme IsoformsPurpose: We have previously shown the involvement of arginase enzyme in retinal neurovascular injury. The present study was undertaken to determine the distinct roles of arginase 1 (A1) and arginase 2 (A2) in neurovascular damage following ischemia/reperfusion (I/R) injury. Methods: We used wild type (WT) mice, A2 knock out mice (A2-/-) and mice lacking one copy of A1 (A1+/-). Western blotting, RT-PCR, vascular digests, immunofluorescence, Propidium Iodide (PI) labeling and electroretinography (ERG) were used to evaluate retinal injury and function. Results: I/R injury caused significant increases in A2 expression along with thinning of the neural retina, decreases in NeuN+ GCL neurons and formation of acellular capillaries. Increases in PI labeling and RIP-3 expression showed that cell death occurred by necroptosis. Neurovascular injury was accompanied by microglial activation along with increased expression of GFAP and impairment of the ERG. Neuronal cell loss, capillary degeneration, necroptosis, gliosis and ERG impairment were all significantly reduced by deletion of A2. On the other hand, A1 deletion exacerbated I/R-induced neuronal and vascular injury and further increased necroptosis and gliosis as compared with WT retinas. Conclusions: This study shows for the first time the different roles of arginase isoforms after I/R insult. I/R-induced necrotic cell death and gliosis are mediated by A2, whereas upregulation of A1 may play a role in limiting the pathology.