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, Ying Chao Chang, Yi Fang Tu, Chao Ching Huang

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Abstract

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.

Original languageEnglish
Pages (from-to)4356-4368
Number of pages13
JournalJournal of Neuroscience
Volume29
Issue number14
DOIs
Publication statusPublished - Apr 8 2009
Externally publishedYes

Fingerprint

Cyclic AMP Response Element-Binding Protein
Vascular Endothelial Growth Factor Receptor
Vascular Endothelial Growth Factor A
Endothelial Cells
Phosphorylation
Neurons
Oxygen
Ligation
Glucose
Oligodeoxyribonucleotides
Arteries
Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factor Receptor-2
Cerebrum
Mutant Proteins
Neutralizing Antibodies
Carotid Arteries
Cerebral Cortex
Serine
Cell Death

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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title = "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",
abstract = "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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T1 - 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

AU - Lee, Hsueh Te

AU - Chang, Ying Chao

AU - Tu, Yi Fang

AU - Huang, Chao Ching

PY - 2009/4/8

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N2 - 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.

AB - 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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