Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 183, Issue 3, Pages 918-929Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2013.05.031
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Funding
- Wellcome Trust [079736, 058083]
- Richard Bright VEGF-A Research Trust
- Alzheimers Research UK [ART-EG2005B-1] Funding Source: researchfish
- Diabetes UK [12/0004538] Funding Source: researchfish
- Medical Research Council [G1000863] Funding Source: researchfish
- MRC [G1000863] Funding Source: UKRI
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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.
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