Society for Neuroscience, Location: Washington
Author:
Abstract:
Reduced VEGF levels cause motor neuron degeneration in mice, whereas delivery of VEGF exerts therapeutic effects in mouse models for ALS, at least partly by exerting direct neurotrophic effects. VEGF has also potent therapeutic effects in diabetic and chemotherapy-induced sensory neuropathies, but these effects have been attributed to the vessel growth and perfusion-promoting effects of VEGF. To test whether direct neuroprotective effects on sensory nerves could also explain the therapeutic effects of VEGF in neuropathies, VEGF was subplantarily delivered to rats suffering from Taxol-induced neuropathy. VEGF treatment potently reduced sensory neuropathies and its effects were similar in size to those of archetypical growth factors. VEGF also protected sensory neurons against neuronal stress induced by Taxol. Mice overexpressing the VEGF-receptor Flk1 in neurons developed a milder sensory deficit after Taxol challenge, whereas mice overexpressing a dominant-negative Flk1 in neurons performed worse after Taxol challenge and failed to respond to VEGF delivery. These effects were observed at the functional level and confirmed by multiphoton-imaging of sensory axons in Thy:YFP mice. Thus, VEGF exerts therapeutic effects in neuropathies directly by stimulating Flk1 on neurons. Delivery of VEGF inhibitors, which are used as anti-angiogenic molecules in cancer, to WT mice induced mechanical hyperalgesia as determined by a Von Frey aesthesiometer. Furthermore, when delivered to mice with Taxol-induced neuropathies, VEGF inhibition aggravated the neuropathic phenotype. Overall, these data indicate that VEGF exerts direct neurotrophic effects on sensory neurons and that VEGF-inhibitors should be applied with care.