Arginase contributes to endothelial cell oxidative stress in response to plasma from women with preeclampsia

Aims Preeclampsia is a hypertensive disorder characterized by vascular oxidative stress. Decreased availability of the vasodilator nitric oxide (NO) has been postulated to be involved in the pathophysiology of this disorder. Arginase, an enzyme that competes with nitric oxide synthase (NOS) for L-arginine, not only reduces NO formation but also increases superoxide production by NOS. In placenta of preeclamptic women, arginase upregulation has been shown to be increased and contributes to superoxide formation via uncoupling of NOS. However, the role of arginase in the maternal vasculature is not clear. We hypothesized that arginase would be upregulated in the maternal vasculature of women with preeclampsia and contribute to oxidative stress within the endothelium. Methods and results We observed increased arginase expression in the maternal vasculature of women with preeclampsia compared with normotensive pregnant women. Furthermore, human umbilical vein endothelial cells treated with 2% plasma from preeclamptic women show increased arginase II expression and activity that was reduced by a peroxynitrite scavenger. Also, both 3-morpholino sydnonimine and exogenous peroxynitrite increased arginase expression and activity. Preeclamptic plasma treatment increased superoxide and peroxynitrite levels. Superoxide levels were significantly reduced after arginase and NOS inhibition with [(S)-(2-boronoethyl)-L-cysteine] and N-(R)-nitro-L-arginine methyl ester, respectively, but peroxynitrite levels were in fact increased after arginase inhibition. Moreover, in the presence of preeclamptic plasma, L-arginine supplementation increased peroxynitrite formation during arginase inhibition. Conclusion Increased arginase expression in preeclampsia can induce uncoupling of NOS as a source of superoxide in the maternal vasculature in preeclampsia. However, L-arginine supplementation in the face of oxidative stress could lead to a further increase in peroxynitrite.