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.

中风是死亡和长期残疾的主要原因，大多数研究主要集中在保护神经元的努力上。但是，失败的临床试验表明，针对神经元中单一靶标的疗法可能还不够，而且内皮细胞和神经胶质细胞的参与程度也被低估了。星形胶质细胞是大脑中ApoE的主要来源，内皮细胞表达高水平的ApoE受体。因此，ApoE可能介导星形胶质细胞和内皮细胞之间的相互作用。为了探讨ApoE介导的星形胶质细胞-内皮细胞相互作用是否以及如何促进中风的发病机理，我们使用氧气和葡萄糖剥夺-复氧（OGD-R）作为中风模型，并研究了OGD-R对星形胶质细胞-内皮细胞的影响本研究中的共培养。我们发现，OGD-R会导致内皮细胞受到各种损害，包括细胞活力受损，ROS水平升高，胱天蛋白酶活性增强和凋亡率升高。同时，小鼠星形胶质细胞可以分泌ApoE激活内皮细胞中的PI3K / eNOS信号传导，从而防止OGD-R诱导的损伤。此外，OGD-R在星形胶质细胞-内皮细胞共培养物中诱导ApoE的下调，而褪黑素通过pCREB途径恢复星形细胞ApoE的表达并在OGD-R处理的共培养物中保护内皮细胞。我们的研究提供了证据，表明在OGD-R条件下星形胶质细胞可以通过ApoE保护内皮细胞，而褪黑激素可以诱导ApoE表达来保护内皮细胞。小鼠星形胶质细胞可以分泌ApoE激活内皮细胞中的PI3K / eNOS信号传导，从而防止OGD-R诱导的损伤。此外，OGD-R在星形胶质细胞-内皮细胞共培养物中诱导ApoE的下调，而褪黑素通过pCREB途径恢复星形细胞ApoE的表达并在OGD-R处理的共培养物中保护内皮细胞。我们的研究提供了证据，表明在OGD-R条件下星形胶质细胞可以通过ApoE保护内皮细胞，而褪黑激素可以诱导ApoE表达来保护内皮细胞。小鼠星形胶质细胞可以分泌ApoE激活内皮细胞中的PI3K / eNOS信号传导，从而防止OGD-R诱导的损伤。此外，OGD-R在星形胶质细胞-内皮细胞共培养物中诱导ApoE的下调，而褪黑素通过pCREB途径恢复星形细胞ApoE的表达并在OGD-R处理的共培养物中保护内皮细胞。我们的研究提供了证据，表明在OGD-R条件下星形胶质细胞可以通过ApoE保护内皮细胞，而褪黑激素可以诱导ApoE表达来保护内皮细胞。OGD-R在星形胶质细胞-内皮细胞共培养物中诱导ApoE的下调，而褪黑素通过pCREB途径恢复星形细胞ApoE的表达并在OGD-R处理的共培养物中保护内皮细胞。我们的研究提供了证据，表明在OGD-R条件下星形胶质细胞可以通过ApoE保护内皮细胞，而褪黑激素可以诱导ApoE表达来保护内皮细胞。OGD-R在星形胶质细胞-内皮细胞共培养物中诱导ApoE的下调，而褪黑素通过pCREB途径恢复星形细胞ApoE的表达并在OGD-R处理的共培养物中保护内皮细胞。我们的研究提供了证据，表明在OGD-R条件下星形胶质细胞可以通过ApoE保护内皮细胞，而褪黑激素可以诱导ApoE表达来保护内皮细胞。