VEGF-A(165)b Is an Endogenous Neuroprotective Splice Isoform of Vascular Endothelial Growth Factor A in Vivo and in Vitro

Nick Beazley-Long, Jing Hua, Thomas Jehle, Richard P. Hulse, Rick Dersch, Christina Lehrling, Heather Bevan, Yan Qiu, Wolf A. Lagreze, David Wynick, Amanda J. Churchill, Patrick Kehoe, Steven J. Harper, Dave O Bates, Lucy F. Donaldson

Research output: Contribution to journalArticle (Academic Journal)peer-review

69 Citations (Scopus)

Abstract

Vascular endothelial growth factor (VEGF) A is generated as two isoform families by alternative RNA splicing, represented by VEGF-A(165)a and VEGF-A(165)b. These isoforms have opposing actions on vascular permeability, angiogenesis, and vasodilatation. The proangiogenic VEGF-A(165)a isoform is neuroprotective in hippocampal, dorsal root ganglia, and retinal neurons, but its propermeabitity, vaso-dilatatory, and angiogenic properties limit its therapeutic usefulness. In contrast, a neuroprotective effect of endogenous VEGF-A(165)b on neurons would be advantageous for neurodegenerative pathologies. Endogenous expression of human and rat VEGF-A(165)b was detected in hippocampal and cortical neurons. VEGF-A(165)b formed a significant proportion of total VEGF-A in rat brain. Recombinant human VEGF-A(165)b exerted neuroprotective effects in response to multiple insults, including glutamatergic excitotoxicity in hippocampal neurons, chemotherapy-induced cytotoxicity of dorsal root ganglion neurons, and retinal ganglion cells (RGCs) in rat retinal ischemia-reperfusion injury in vivo. Neuroprotection was dependent on VEGFR2 and MEK1/2 activation but not on p38 or phosphatidylinositol 3 kinase activation. Recombinant human VEGF-A(165)b is a neuroprotective agent that effectively. protects both peripheral and central neurons in vivo and in vitro through VEGFR2, MEK1/2, and inhibition of caspase-3 induction. VEGF-A(165)b may be therapeutically useful for pathologies that involve neuronal damage, including hippocampal neurodegeneration, glaucoma diabetic retinopathy, and peripheral neuropathy. The endogenous nature of VEGF-A(165)b expression suggests that non-isoform-specific inhibition of VEGF-A (for antiangiogenic reasons) may be damaging to retinal and sensory neurons.

Original languageEnglish
Pages (from-to)918-929
Number of pages12
JournalAmerican Journal of Pathology
Volume183
Issue number3
DOIs
Publication statusPublished - Sep 2013

Bibliographical note

Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Keywords

  • ANGIOGENIC VEGF ISOFORM
  • GANGLION-CELL DEATH
  • GENE-TRANSFER
  • NEUROPATHIC PAIN
  • KINASE-ACTIVITY
  • TUMOR-GROWTH
  • RAT RETINA
  • VEGF(165)B
  • EXPRESSION
  • SURVIVAL

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