FIGURE 9.

Schematic model of signaling pathways that acutely regulate vascular actions of DHEA. As described previously (19), DHEA acutely activates PI 3-kinase/Akt/endothelial nitric-oxide synthase (eNOS) to stimulate production of the vasodilator NO. In addition, DHEA activates MAPK signaling to stimulate secretion of the vasoconstrictor ET-1. In the present study we demonstrated that DHEA acutely stimulates phosphorylation of FoxO1 using signaling pathways involving PKA and PI 3-kinase. Phosphorylated FoxO1 is excluded from the nucleus and translocated to the cytosol where it is unable to bind and activate the ET-1 promoter. Thus, a complex signaling network regulates opposing vascular actions of DHEA, and the net vasoactive action of DHEA is determined in part by the balance between PI 3-kinase- and MAPK-dependent signaling.