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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/11955

Title: Neuronal FLT1 receptor and its selective ligand VEGF-B protect against retrograde degeneration of sensory neurons
Authors: Dhondt, Joke
Verheyen, An
Nuydens, Rony
Buysschaert, Ian
Poesen, Koen
Van Geyte, Katie
Beerens, Manu
Shibuya, Masabumi
Haigh, Jody J.
Carmeliet, Peter
Lambrechts, Diether
Issue Date: 2011
Citation: FASEB JOURNAL, 25(5). p. 1461-1473
Abstract: Even though VEGF-B is a homologue of the potent angiogenic factor VEGF, its angiogenic activities have been controversial. Intrigued by findings that VEGF-B may also affect neuronal cells, we assessed the neuroprotective and vasculoprotective effects of VEGF-B in the skin, in which vessels and nerves are functionally intertwined. Although VEGF-B and its FLT1 receptor were prominently expressed in dorsal root ganglion (DRG) neurons innervating the hindlimb skin, they were not essential for nerve function or vascularization of the skin. However, primary DRG cultures lacking VEGF-B or FLT1 exhibited increased neuronal stress and were more susceptible to paclitaxel-induced cell death. Concomitantly, mice lacking VEGF-B or a functional FLT1 developed more retrograde degeneration of sensory neurons in a model of distal neuropathy. On the other hand, the addition of the VEGF-B isoform, VEGF-B-186, to DRG cultures antagonized neuronal stress, maintained the mitochondrial membrane potential and stimulated neuronal survival. Mice overexpressing VEGF-B-186 or FLT1 selectively in neurons were protected against the distal neuropathy, whereas exogenous VEGF-B-186, either delivered by gene transfer or as a recombinant factor, was protective by directly affecting sensory neurons and not the surrounding vasculature. Overall, this indicates that VEGF-B, instead of acting as an angiogenic factor, exerts direct neuroprotective effects through FLT1. These findings also suggest a clinically relevant role for VEGF-B in preventing distal neuropathies.-Dhondt, J., Peeraer, E., Verheyen, A., Nuydens, R., Buysschaert, I., Poesen, K., Van Geyte, K., Beerens, M., Shibuya, M., Haigh, J. J., Meert, T., Carmeliet, P., Lambrechts, D. Neuronal FLT1 receptor and its selective ligand VEGF-B protect against retrograde degeneration of sensory neurons. FASEB J. 25, 1461-1473 (2011). www.fasebj.org
Notes: [Lambrechts, Diether] Katholieke Univ Leuven, Vesalius Res Ctr, Flanders Inst Biotechnol, B-3000 Louvain, Belgium. [Dhondt, Joke; Verheyen, An; Buysschaert, Ian; Poesen, Koen; Van Geyte, Katie; Beerens, Manu; Carmeliet, Peter; Lambrechts, Diether] VIB, Vesalius Res Ctr, Louvain, Belgium. [Peeraer, Eve; Verheyen, An; Nuydens, Rony; Meert, Theo] Johnson & Johnson Pharmaceut Res & Dev, Dept Neurosci, Beerse, Belgium. [Peeraer, Eve] Univ Hasselt, Biomed Res Inst, Diepenbeek, Belgium. [Shibuya, Masabumi] Tokyo Med & Dent Univ, Dept Mol Oncol, Tokyo, Japan. [Haigh, Jody J.] VIB, Dept Mol Biomed Res, Vasc Cell Biol Unit, Ghent, Belgium. [Haigh, Jody J.] Univ Ghent, Dept Biomed Mol Biol, B-9000 Ghent, Belgium. diether.lambrechts@vib-kuleuven.be
URI: http://hdl.handle.net/1942/11955
DOI: 10.1096/fj.10-170944
ISI #: 000290023800005
ISSN: 0892-6638
Category: A1
Type: Journal Contribution
Validation: ecoom, 2012
Appears in Collections: Research publications

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