CREB activation mediates VEGF-A's protection of neurons and cerebral vascular endothelial cells
CREB activation mediates VEGF-A's protection of neurons and cerebral vascular endothelial cells
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DOI：
10.1111/j.1471-4159.2010.06584.x
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发表时间：
2010-04-01
影响因子：
4.7
通讯作者：
Huang, Chao-Ching
中科院分区：
文献类型：
--
作者：
Lee, Hsueh-Te;Chang, Ying-Chao;Huang, Chao-Ching
新生儿脑缺血可引起严重的神经发育后遗症.针对神经元和脉管系统中表达的特异性转录因子设计的药理学试剂可以提供针对HI的强有力的治疗。血管内皮生长因子-A（VEGF-A）和cAMP反应元件结合蛋白（CREB）都是学习和记忆以及神经系统存活的基础。我们研究了CREB激活是否是VEGF-A保护神经元和脑血管内皮细胞的一个共同途径。VEGF-A用于大鼠幼仔的HI模型和永生化H19-7神经元和b.End3脑血管内皮细胞的氧-葡萄糖剥夺（OGD）模型。我们发现，VEGF-A激活VEGF受体-2（VEGFR-2），磷酸化神经元和内皮细胞中的CREB，并保护大鼠免受HI，并且在VEGF-A之前抑制VEGFR-2会降低VEGF-A的保护作用。VEGF-A还上调VEGFR-2和磷酸化CREB，并保护H19-7神经元和b.End3内皮细胞免受OGD。分别抑制VEGFR-2和细胞外信号调节激酶（ERK），减少VEGF-A诱导的CREB磷酸化和H19-7和b.End3细胞对OGD的保护。用丝氨酸-133磷酸化突变CREB转染H19-7和b.End3细胞也抑制了VEGF-A对两种类型细胞的保护作用。我们得出结论，通过VEGFR-2/ERK信号传导的CREB磷酸化是VEGF-A保护神经元和血管内皮细胞的共同途径。
P>Hypoxic ischemia (HI) in neonates causes significant neurodevelopmental sequelae. Pharmacological agents designed to target specific transcription factors expressed in neurons and vasculature may provide powerful therapy against HI. Vascular endothelial growth factor-A (VEGF-A) and cAMP response element-binding protein (CREB) both underlie learning and memory, and survival of the nervous system. We examined whether CREB activation is a shared pathway underlying VEGF-A's protection in neurons and cerebral vascular endothelial cells. VEGF-A was used in a HI model of rat pups and in oxygen-glucose-deprivation (OGD) models of immortalized H19-7 neurons and b.End3 cerebral vascular endothelial cells. We found that VEGF-A activated VEGF receptor-2 (VEGFR-2), phosphorylated CREB in neurons and endothelial cells, and protected against HI, and inhibiting VEGFR-2 before VEGF-A reduced the protective effect of VEGF-A in rat pups. VEGF-A also up-regulated VEGFR-2 and phosphorylated CREB, and protected H19-7 neurons and b.End3 endothelial cells against OGD. Inhibiting VEGFR-2 and extracellular signal-regulated kinase (ERK), respectively, reduced VEGF-A-induced CREB phosphorylation and protection of H19-7 and b.End3 cells against OGD. Transfecting H19-7 and b.End3 cells with a serine-133 phosphorylation mutant CREB also inhibited VEGF-A's protection of both types of cells. We conclude that CREB phosphorylation through VEGFR-2/ERK signaling is the shared pathway that underlies VEGF-A's protection of neurons and vascular endothelial cells.