Stimulation of tetrahydrobiopterin synthesis by 17β-estradiol in brain microvascular endothelial cells

The purpose of this study was to examine whether 17 beta -estradiol stimulates the synthesis of tetrahydrobiopterin (BH4), which is one of the cofactors of nitric oxide (NO) synthase, in mouse brain microvascular endothelial cells. Addition of 17 beta -estradiol to endothelial cells time- and concentration-dependently increased intracellular BH, level. 17 beta -Estradiol also stimulated the mRNA level of GTP-cydohydrolase I (GTPCH), which is a rate-limiting enzyme of the de novo BH, synthetic pathway. In addition, the 17 beta -estradiol-induced expression of GTPCH mRNA was strongly attenuated by treatment with an inhibitor of 17 beta -estradiol receptor 4-hydroxy-tamoxifen. These results suggest that 17 beta -estradiol stimulates BH, synthesis through the induction of GTPCH by tamoxifen-sensitive receptor in vascular endothelial cells. The 17 beta -estradiol-induced increase in BH, level might be implicated in not only NO production, but also protective effects of 17 beta -estradiol against ischemic brain damage and atherosclerosis, since BH4 is an intracellular antioxidant.