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Jutamas Suwanpradid, Zhimin Xu, Subhadra P. Narayanan, Robert W. Caldwell, Ruth B. Caldwell; Arginase 2 Deficiency Limits Microglia/Macrophage Activation and Prevents Hyperoxia-induced Vascular Injury in the Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5882.
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Excessive activity of the urea cycle enzyme arginase has been suggested to play an important role in vascular injury during cardiovascular diseases. Our lab is investigating whether this enzyme could serve as a therapeutic target in retinal vascular disease. Our previous studies showed that deletion of arginase 2 (A2) enhances physiological vascular repair in a mouse model of oxygen-induced retinopathy. Now, we have examined the involvement of A2 in hyperoxia-induced vascular injury and explored the role of macrophage/microglia in the pathological process.
Mice (A2ko, WT) were placed in 70% oxygen from p7-p12 and then returned to room air. The hyperoxia exposure causes obliteration of the developing vessels which leads to a condition of relative ischemia upon return to normal oxygen environment. Mice were sacrificed at different times during or after the hyperoxia treatment and their retinas were processed to determine the effects of arginase deletion on vaso-obliteration in relation to the distribution of microglia/macrophage cells and oxidative stress.
Measurement of the central avascular zone after 24 hrs of hyperoxia treatment showed that the area of vaso-obliteration in the retinas of A2ko mice was significantly smaller than that in the WT (26% vs 31%, P<0.05) indicating that vascular survival is improved. The vasoprotective effect of A2 deletion continued during the hypoxic phase and at p17 the avascular area and average size of neovascular tufts were significantly reduced (by 2.2 and 4.7 fold, respectively, P<0.05). This vasoprotective effect in the A2ko retina was associated with a decrease in the formation of superoxide and peroxynitrite along with a significant increase in the ratio of resting microglia to activated microglia/macrophage as compared with the retinas of hyperoxia-treated WT mice (P<0.05).
Arginase 2 plays a key role in hyperoxia-induced retinal vascular injury through a mechanism involving formation of superoxide and peroxynitrite and activation of microglia/macrophage cells.
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