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In‐vivo genetic inactivation of CuZn‐superoxide dismutase (SOD1) prevents vascular protective effects of erythropoietin

Previous studies demonstrated that treatment with erythropoietin (EPO) prevents endothelial dysfunction and medial thickening after wire‐induced injury of mouse carotid artery. In the present study, we tested the hypothesis that stimulatory effect of EPO on expression and activity of SOD1 is an important mechanism underlying the vascular protective effect of EPO. This hypothesis was based on observation that treatment with recombinant human EPO (1000 U/kg, s.c., biweekly for 2 weeks) significantly enhanced SOD1 protein expression by 31% in arteries of wild‐type mice (P<0.05; n=3). Analysis of the vascular effects of EPO was performed in SOD1‐deficient (SOD1−/−) mice. Two weeks after wire‐induced injury vascular reactivity of carotid arteries was studied in‐vitro under pressurized condition, and the arteries were histologically assessed. Endothelium‐dependent relaxations to acetylcholine were impaired in carotid arteries of SOD1−/− mice (P<0.05 vs. control SOD1−/− mice; n=7‐8) while endothelium‐independent relaxations to nitric oxide donor, DEA‐NONOate, were unaffected. This was associated with increased medial cross sectional area (33±2 x10−3 mm2; P<0.05 vs. controls: 28±1 x10−3 mm2; n=9‐10). Treatment with EPO did not affect endothelial dysfunction or medial thickening of injured carotid arteries in SOD1−/− mice (n=7‐10). Furthermore, EPO did not prevent increased superoxide anion production in aortas of SOD1−/− mice. These findings suggest that the vascular protective effects of EPO are dependent on activation of SOD1.