The role of vascular endothelial growth factor in major depression

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor under physiological and pathological conditions, including tumor angiogenesis. Recently, the effects of VEGF on neurons have been reported. VEGF and its high-affinity tyrosine kinase receptors, VEGFR1 and VEGFR2, are expressed in specific brain regions. In addition, VEGF has been suggested to play an important role in the cross-talk between endothelial cells and neuronal progenitors in the hippocampus, indicating that VEGF may stimulate hippocampal neurogenesis. Neurotrophic factors and neurogenesis are associated with the development of major depression and play essential roles in mediating the therapeutic response to antidepressants. Several animal studies have shown that chronic stress decreased the expression of VEGF and VEGFR2 in granular cells. There is also evidence suggesting that antidepressant treatment-induced neurogenesis requires VEGF signaling through VEGFR2. Clinical studies, however, have been controversial. Some researchers reported no significant difference in serum/plasma VEGF level between patients with major depressive disorder (MDD) and healthy controls, whereas others found that VEGF level was significantly higher in MDD patients than in controls. Furthermore, psycho-oncology studies have shown that higher VEGF levels in serum and tumor cells are associated with depressive states in patients with tumors. Consistently, noradrenaline, a stress hormone, significantly enhanced VEGF production in various tumor cells in vitro, and this effect was blocked by beta-blockers. These findings suggest that stress or stress-related mediators promote VEGF production in tumors. VEGF in the central nervous system (CNS), however, showed a distinct pattern of changes compared to serum (somatic) VEGF. Chronic stress is known to decrease the production and signaling of VEGF in the CNS, while stress increases the production of VEGF by somatic tumor cells. The mechanism responsible for the changes in VEGF levels remains elusive and needs further investigation.