Figure 1.

FOXO3 is an integrator of multiple signaling pathways to maintain vascular homeostasis. Under normal conditions, FOXO3 is inactive due to the negative regulation by IIS-PI3K-Akt pathway. Akt phosphorylates FOXO3 at three highly conserved residues T32, S253, and S315, thereby establishing docking sites for the chaperone protein 14-3-3 and preventing it from re-entering the nucleus. PTEN antagonizes the effect of PI3K and induces FOXO3 activation. When cells are exposed to stress, including growth factor deprivation, metabolic stress, and oxidative stress, FOXO3 translocates into the nucleus and exhibits increased transcriptional activity. FOXO3 regulates a number of cellular processes, including apoptosis, autophagy, oxidative resistance, and metabolism, all of which are involved in the pathological process of vascular aging.