Spatiotemporal variations of vascular endothelial growth factor in the brain of diabetic cognitive impairment

Although it is feared that diabetes-induced cognitive impairment (DCI) will become a major clinical problem worldwide in the future, its detailed pathological mechanism is not well known. Because patients with diabetes have various complications of vascular disease, vascular disorders in the brain are considered to be one of the main mechanisms of DCI. Mounting evidence suggests that the vascular endothelial growth factor (VEGF) family plays a crucial role in the development of DCI. In this review, we summarized the changes and functions of VEGF during the development of DCI, and speculated that it was characterized by spatiotemporal variations in DCI progression. Considering the complexity of DCI pathogenesis and the diversity of VEGF function, we focused on the interrelationship of DCI and VEGF spatiotemporal variations during DCI development. During the progression of DCI, hyperglycemia, abnormal brain insulin signals, advanced glycation end products (AGEs) and consequently hypoxia, oxidative stress, and inflammation are the main pathophysiological changes; hypoxia-inducible factor (HIF), reactive oxygen species (ROS), and nuclear factor kappa beta (NF-κB) play major roles in DCI-related VEGF spatiotemporal regulation. Furthermore, spatiotemporal variations in VEGF-mediated pathological cerebral neovascularization, repair and regeneration of dural lymphatic vessels, increased blood-brain barrier (BBB) permeability and slight neuroprotection are increasing emphasized as potential targets in the treatment of DCI.