title: VEGF-A165b is an endogenous neuroprotective splice isoform of vascular endothelial growth factor A in vivo and in vitro.
abstract: Vascular endothelial growth factor (VEGF) A is generated as two isoform families by alternative RNA splicing, represented by VEGF-A165a and VEGF-A165b. These isoforms have opposing actions on vascular permeability, angiogenesis, and vasodilatation. The proangiogenic VEGF-A165a isoform is neuroprotective in hippocampal, dorsal root ganglia, and retinal neurons, but its propermeability, vasodilatatory, and angiogenic properties limit its therapeutic usefulness. In contrast, a neuroprotective effect of endogenous VEGF-A165b on neurons would be advantageous for neurodegenerative pathologies. Endogenous expression of human and rat VEGF-A165b was detected in hippocampal and cortical neurons. VEGF-A165b formed a significant proportion of total VEGF-A in rat brain. Recombinant human VEGF-A165b 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-A165b 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-A165b may be therapeutically useful for pathologies that involve neuronal damage, including hippocampal neurodegeneration, glaucoma diabetic retinopathy, and peripheral neuropathy. The endogenous nature of VEGF-A165b expression suggests that non-isoform-specific inhibition of VEGF-A (for antiangiogenic reasons) may be damaging to retinal and sensory neurons.
authors.affiliation: Microvascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Beazley-Long
authors.forename: Jing
authors.initials: J
authors.lastname: Hua
authors.forename: Thomas
authors.initials: T
authors.lastname: Jehle
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hulse
authors.forename: Rick
authors.initials: R
authors.lastname: Dersch
authors.forename: Christina
authors.initials: C
authors.lastname: Lehrling
authors.forename: Heather
authors.initials: H
authors.lastname: Bevan
authors.forename: Yan
authors.initials: Y
authors.lastname: Qiu
authors.forename: Wolf A
authors.initials: WA
authors.lastname: Lagrèze
authors.forename: David
authors.initials: D
authors.lastname: Wynick
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Churchill
authors.forename: Patrick
authors.initials: P
authors.lastname: Kehoe
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Harper
authors.forename: David O
authors.initials: DO
authors.lastname: Bates
authors.forename: Lucy F
authors.initials: LF
authors.lastname: Donaldson
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D019610:Cytoprotection / Q000187:drug effects; D005727:Ganglia, Spinal / Q000473:pathology; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D020033:Protein Isoforms; D051381:Rats; D017208:Rats, Wistar; D055351:Retinal Neurons / Q000187:drug effects / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D009498:Neurotoxins; D020033:Protein Isoforms; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D018698:Glutamic Acid; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2