Modulation of human endothelial cell tetrahydrobiopterin synthesis by activating and deactivating cytokines: new perspectives on endothelium-derived relaxing factor.

Endothelial cells, through soluble mediators, play an important role in the regulation of the vascular tone. In the present paper we investigated whether endothelial tetrahydrobiopterin (BH4), an obligatory cofactor of nitric oxide (NO) synthase, could serve as such a regulatory mediator. By studying the human vascular endothelial hybrid cells EA hy 926, we found that 1) BH4 biosynthesis is highly regulated (70-fold) by activating and deactivating cytokines; that 2) up to 90% of the induced BH4 is released by activated endothelium, and 3) while intracellular BH4 could be related to cyclic GMP concentrations within the endothelial cells, the bulk of BH4 (up to 90 pmol/10(6) cells) appears not to serve endothelial cell requirements. Activation and deactivation of BH4 synthesis by cytokines was paralleled by other endothelial cell responses reflecting their activity. We propose that BH4 serves as an endothelial mediator augmenting the activity of cytokine-inducible NO synthase in vascular smooth muscle cells. BH4 could thereby account for endothelium-derived relaxing factor activity.