VEGF-A165b is an endogenous neuroprotective splice isoform of vascular endothelial growth factor A in vivo and in vitro

Beazley-Long, N., Hua, J., Jehle, T., Hulse, R.P. ORCID: 0000-0002-5193-9822, Dersch, R., Lehrling, C., Bevan, H., Qiu, Y., Lagrèze, W.A., Wynick, D., Churchill, A.J., Kehoe, P., Harper, S.J., Bates, D.O. and Donaldson, L.F., 2013. VEGF-A165b is an endogenous neuroprotective splice isoform of vascular endothelial growth factor A in vivo and in vitro. The American Journal of Pathology, 183 (3), pp. 918-929. ISSN 0002-9440

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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.

Item Type: Journal article
Publication Title: The American Journal of Pathology
Creators: Beazley-Long, N., Hua, J., Jehle, T., Hulse, R.P., Dersch, R., Lehrling, C., Bevan, H., Qiu, Y., Lagrèze, W.A., Wynick, D., Churchill, A.J., Kehoe, P., Harper, S.J., Bates, D.O. and Donaldson, L.F.
Publisher: Elsevier
Date: September 2013
Volume: 183
Number: 3
ISSN: 0002-9440
Identifiers:
NumberType
10.1016/j.ajpath.2013.05.031DOI
Divisions: Schools > School of Science and Technology
Depositing User: Jonathan Gallacher
Date Added: 09 Jan 2018 10:02
Last Modified: 20 Mar 2018 11:55
URI: http://irep.ntu.ac.uk/id/eprint/32353

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