Melatonin-induced ApoE expression in mouse astrocytes protects endothelial cells from OGD-R induced injuries

Stroke is a leading reason of death and long-term disability, and most studies mainly focus on efforts to protect neurons. However, failed clinical trials suggest that therapies against single target in neurons may not be sufficient and the involvement of endothelial cells and glial cells have been underestimated. Astrocytes are the major source of ApoE in the brain and endothelial cells express high level of ApoE receptors. Thus, ApoE may mediate the interaction between astrocytes and endothelial cells. To address whether and how ApoE-mediated astrocytes–endothelial cells interaction contributes to the pathogenesis of stroke, we used oxygen and glucose deprivation-reoxygenation (OGD-R) as a stroke model and investigated the effects of OGD-R on astrocytes-endothelial cell co-cultures in the current study. We find that OGD-R leads to various damages to endothelial cells, including compromised cell viability, increased ROS level, enhanced caspase activity, and higher apoptotic rate. Meanwhile, mouse astrocytes could secrete ApoE to activate PI3K/eNOS signaling in endothelial cells to prevent OGD-R induced injuries. In addition, OGD-R induces down-regulation of ApoE in astrocyte–endothelial cell co-cultures while melatonin restores astrocytic ApoE expression via pCREB pathway and protects endothelial cell in OGD-R treated co-cultures. Our study provides evidence that astrocytes could protect endothelial cells via ApoE in OGD-R condition and Melatonin could induce ApoE expression to protect endothelial cells.