Zinc regulates a specific subpopulation of VEGFA plus microglia to improve the hypoxic microenvironment for functional recovery after spinal cord injury

Introduction: Spinal cord injury (SCI) is a central nervous system injury that is primarily traumatic and manifests as autonomic dysfunction below the level of injury. Our previous studies have found that zinc ions have important effects on the nervous system and nerve repair, promoting autophagy and reducing inflammatory responses. However, the role of zinc ions in vascular regeneration is unclear. Aims: We investigated the effect of zinc ions after spinal cord injury from the perspective of a hypoxic microenvironment, and elucidated the role of VEGF-A secreted by microglia for vascular regeneration after spinal cord injury, providing new ideas for the treatment of spinal cord injury. Results: Zinc promotes functional recovery after spinal cord injury by regulating VEGF-A secretion from microglia. On the one hand, VEGF-A secreted by microglia promotes angiogenesis through the PI3K/AKT/Bcl-2 pathway and improves the hypoxic microenvironment after spinal cord injury. On the other hand, VEGF-A secreted by microglia was positively correlated with platelet endothelial cell adhesion molecule-1 (CD31), and zinc could increase the association between microglia and blood vessels. Conclusion: Zinc promoted microglia secretion of VEGF-A, increased vascular endothelial cell proliferation and migration through the PI3K/AKT/Bcl-2 pathway, and inhibited microglia apoptosis.