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The Journal of Neuroscience, April 8, 2009, 29(14):4356-4368; doi:10.1523/JNEUROSCI.5497-08.2009

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Development/Plasticity/Repair
VEGF-A/VEGFR-2 Signaling Leading to cAMP Response Element-Binding Protein Phosphorylation Is a Shared Pathway Underlying the Protective Effect of Preconditioning on Neurons and Endothelial Cells

Hsueh-Te Lee,¹ Ying-Chao Chang,⁴ Yi-Fang Tu,^2,3 and Chao-Ching Huang^1,2

¹Department of Pediatrics, ²Institute of Clinical Medicine, and ³Department of Emergency Medicine, National Cheng Kung University Hospital, Tainan 70428, Taiwan, and ⁴Department of Pediatrics, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan

Correspondence should be addressed to Dr. Chao-Ching Huang, Department of Pediatrics, National Cheng Kung University Hospital, 138 Sheng-Li Road, Tainan City 704, Taiwan. Email: huangped{at}mail.ncku.edu.tw

Preconditioning protects endothelial cells as well as neurons from ischemic injury. In 7-d-old rat pups, ligating the carotid artery 1 h before hypoxia damaged the ipsilateral cerebral hemisphere; in contrast, ligating the artery 24 h before hypoxia provided complete neuroprotection. The protective effect of the 24 h artery ligation preconditioning model requires the activation of cAMP response element-binding protein (CREB). We tested the hypothesis that vascular endothelial growth factor (VEGF)-A/VEGF receptor-2 (VEGFR-2) signaling that leads to CREB activation is the shared pathway underlying the protective effect of preconditioning in neurons and endothelial cells. VEGF-A, VEGFR-1, or VEGFR-2 was inhibited by antisense oligodeoxynucleotides (ODNs) in vivo and by a VEGF-A neutralizing antibody or VEGFR-2 inhibitor in vitro. CREB phosphorylation (pCREB) and VEGF-A and VEGFR-2 expression were increased and colocalized in vascular endothelial cells and neurons in the ipsilateral cerebral cortex 24 h after ligation. The antisense ODN blockades of VEGF-A and VEGFR-2 decreased pCREB and reduced the protection of 24 h ligation preconditioning. Furthermore, oxygen-glucose deprivation (OGD) preconditioning upregulated VEGF-A, VEGFR-2, and pCREB levels and protected immortalized H19-7 neuronal cells and b.End3 vascular endothelial cells against 24 h OGD cell death. Blocking VEGF-A or VEGFR-2 reduced CREB activation and the effects of OGD preconditioning in neuronal cells and endothelial cells. Transfecting a serine-133 phosphorylation mutant CREB also inhibited the protective effect of OGD preconditioning. We conclude that VEGF-A/VEGFR-2 signaling leading to CREB phosphorylation is the shared pathway underlying the preconditioning-induced protective effect in neurons and vascular endothelial cells in the developing brain.

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Received Nov. 14, 2008; revised Dec. 29, 2008; accepted Feb. 24, 2009.

Correspondence should be addressed to Dr. Chao-Ching Huang, Department of Pediatrics, National Cheng Kung University Hospital, 138 Sheng-Li Road, Tainan City 704, Taiwan. Email: huangped{at}mail.ncku.edu.tw

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