Brain angiogenesis in developmental and pathological processes: therapeutic aspects of vascular endothelial growth factor

The angiogenic process in the central nervous system (CNS) is basically regulated by typical angiogenic signaling systems such as vascular endothelial growth factor (VEGF)–VEGF receptors and angiopoietin–Tie receptors. In addition to regular endothelial–pericyte interaction, the CNS vasculature has a unique system of cell to cell communication between endothelial cells and astrocytes which is known as the blood–brain barrier. Among the pathological conditions of the CNS vascular network, stroke is a major disease in which the supply of blood is decreased. Pro‐angiogenic therapy using natural VEGF‐A has so far been unsuccessful, indicating the possible need for a new approach related to upstream or downstream regulators involved in the VEGF‐signaling pathway, or alternate VEGF family members. By contrast, a pathological increase in the blood supply in the CNS is seen in brain tumors, in particular malignant gliomas. In phase II clinical trials, anti‐VEGF therapies have been shown to suppress tumor growth and improve survival rates to some extent. However, tumor invasion and the distant metastasis of gliomas can occur following anti‐angiogenic therapy. Further studies are needed to obtain safer clinical outcomes by developing new strategies with combination therapy using known anti‐angiogenic drugs or by developing unique medicines specifically targeting the blood vessels in brain tumors.