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The Journal of Neuroscience, October 15, 2008, 28(42):10451-10459; doi:10.1523/JNEUROSCI.1092-08.2008

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Neurobiology of Disease
Novel Role for Vascular Endothelial Growth Factor (VEGF) Receptor-1 and Its Ligand VEGF-B in Motor Neuron Degeneration

Koen Poesen,^1,4 * Diether Lambrechts,^1,4 * Philip Van Damme,^3,4 Joke Dhondt,^1,4 Florian Bender,⁵ Nicolas Frank,⁵ Elke Bogaert,^3,4 Bart Claes,^1,4 Line Heylen,^1,4 An Verheyen,^1,4 Katrien Raes,^1,4 Marc Tjwa,^1,4 Ulf Eriksson,⁶ Masabumi Shibuya,⁷ Rony Nuydens,⁸ Ludo Van Den Bosch,^3,4 Theo Meert,⁸ Rudi D'Hooge,² Michael Sendtner,⁵ Wim Robberecht,^3,4 and Peter Carmeliet^1,4

¹Vesalius Research Center, ²Laboratory of Biological Psychology, Department of Psychology, and ³Laboratory of Experimental Neurology, Campus Gasthuisberg, Katholieke Universiteit Leuven, Leuven B-3000, Belgium, ⁴Vesalius Research Center, Flanders Institute for Biotechnology (VIB), Leuven B-3000, Belgium, ⁵Institute for Clinical Neurobiology, University of Würzburg, D-97080 Würzburg, Germany, ⁶Ludwig Institute for Cancer Research, Stockholm Branch, S-171 77 Stockholm, Sweden, ⁷Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo 113-8579, Japan, and ⁸Neuroscience Department, Johnson & Johnson Pharmaceutical Research & Development, Janssen Pharmaceutica, Beerse B-2340, Belgium

Correspondence should be addressed to Dr. Peter Carmeliet, Vesalius Research Center, Flanders Institute for Biotechnology, Campus Gasthuisberg, Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium. Email: peter.carmeliet{at}med.kuleuven.be

Although vascular endothelial growth factor-B (VEGF-B) is a homolog of the angiogenic factor VEGF, it has only minimal angiogenic activity, raising the question of whether this factor has other (more relevant) biological properties. Intrigued by the possibility that VEGF family members affect neuronal cells, we explored whether VEGF-B might have a role in the nervous system. Here, we document that the 60 kDa VEGF-B isoform, VEGF-B¹⁸⁶, is a neuroprotective factor. VEGF-B¹⁸⁶ protected cultured primary motor neurons against degeneration. Mice lacking VEGF-B also developed a more severe form of motor neuron degeneration when intercrossed with mutant SOD1 mice. The in vitro and in vivo effects of VEGF-B¹⁸⁶ were dependent on the tyrosine kinase activities of its receptor, Flt1, in motor neurons. When delivered intracerebroventricularly, VEGF-B¹⁸⁶ prolonged the survival of mutant SOD1 rats. Compared with a similar dose of VEGF, VEGF-B¹⁸⁶ was safer and did not cause vessel growth or blood–brain barrier leakiness. The neuroprotective activity of VEGF-B, in combination with its negligible angiogenic/permeability activity, offers attractive opportunities for the treatment of neurodegenerative diseases.

Key words: ALS; VEGF-B; Flt1; motor neuron degeneration; intracerebroventricular delivery; therapy

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Received Aug. 26, 2008; accepted Aug. 31, 2008.

Correspondence should be addressed to Dr. Peter Carmeliet, Vesalius Research Center, Flanders Institute for Biotechnology, Campus Gasthuisberg, Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium. Email: peter.carmeliet{at}med.kuleuven.be

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				C. Ruiz de Almodovar, D. Lambrechts, M. Mazzone, and P. Carmeliet Role and Therapeutic Potential of VEGF in the Nervous System Physiol Rev, April 1, 2009; 89(2): 607 - 648. [Abstract] [Full Text] [PDF]

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