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Title: VEGF protects sensory axons against a retrograde axonopathy: implications for anti-angiogenic therapies
Authors: Verheyen, An
Peeraer, Eve
Nuydens, Rony
Poesen, Koen
Pintelon, Isabel
Dhondt, Joke
Timmermans, Jean-Pierre
Beerens, Manu
Kieckens, Lena
Hermans, Bart
Carmeliet, Peter
Meert, Theo
Lambrechts, Diether #
Issue Date: 2010
Conference: Belgian Brain Congress location:Brussels date:17-18 September 2010
Abstract: Reduced VEGF levels cause motor neuron degeneration in mice, whereas VEGF delivery exerts therapeutic effects in ALS mouse models, at least partly by direct neurotrophic effects. VEGF also exerts potent therapeutic effects in chemotherapy-induced sensory neuropathies, which have been attributed to its vessel growth and perfusion-promoting effects.
To test whether the therapeutic effect of VEGF is due to a direct effect on sensory nerves, VEGF was subplantarly delivered to rats with Taxol-induced neuropathy. VEGF treatment significantly reduced sensory neuropathy comparable to archetypical growth factors. VEGF also protected sensory neurons in vitro against Taxol induced tubulin hyperacetylation, neuronal stress and cell death.
Mice overexpressing the VEGF-receptor (VEGFR) Flk1 in neurons developed a milder sensory deficit after Taxol challenge, whereas mice overexpressing a dominant-negative Flk1 in neurons performed worse and failed to respond to VEGF delivery. Also in vitro, DRG neurons with Flk1 overexpression were more protected against Taxol induced hyperacetylation and neuronal stress. The positive effects of VEGF were counteracted by TSA and Tubacin, which suggests that VEGF protects sensory neurons in these Taxol models at least partly via HDAC6.
Delivery of VEGFR inhibitors, an anti-angiogenic treatment for cancer, to WT mice induced mechanical allodynia. Furthermore, when delivered to mice with Taxol-induced neuropathy, VEGFR inhibition aggravated the sensory deficits. Overall, these data indicate that VEGF exerts direct neurotrophic effects on sensory neurons through its Flk1 receptor and that VEGFR-inhibitors should be applied with care.
Publication status: published
KU Leuven publication type: AMa
Appears in Collections:Laboratory of Translational Genetics (Vesalius Research Center) (+)
Laboratory of Angiogenesis and Neurovascular Link (Vesalius Research Center) (+)
Vesalius Research Centre (-)
Molecular and Vascular Biology
Animal Research Center
# (joint) last author

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