Regular exercise cures depression-like behavior via VEGF-Flk-1 signaling in chronically stressed mice.

In animals, chronic stress leads to the development of depression-like behavior and decreases neurogenesis and blood vessel density in hippocampus, whereas antidepressants increase adult neurogenesis in hippocampus. Regular exercise training also has antidepressant action and increases hippocampal neurogenesis; however, whether exercise-induced antidepressant action is related to hippocampal microvasculature is unclear. To address this issue, we compared depression-like behavior, blood vessel density, and neurogenesis in hippocampal dentate gyrus between stressed and exercised mice with or without administration of inhibitor of vascular endothelial growth factor (VEGF) receptor. Chronic stress led to the development of depression-like behavior, decreased blood vessel density, and neurogenesis in hippocampus. Regular exercise training improved depression-like behavior, the decrease of hippocampal blood vessel density, and neurogenesis in the stress state, whereas the combination of regular exercise and administration of SU1498, VEGF receptor Flk-1 inhibitor, canceled the exercise-induced antidepressant effect. These findings suggested that the improvement of hippocampal blood vessel and adult neurogenesis via VEGF signaling pathway is necessary for exercise-induced antidepressant effect.