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First published online 26 January 2005
doi: 10.1242/dev.01675

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Peripheral nerve-derived VEGF promotes arterial differentiation via neuropilin 1-mediated positive feedback

¹ Division of Biology 216-76, California Institute of Technology, 1201 E. California Boulevard, Pasadena, CA 91125, USA
² Howard Hughes Medical Institute, California Institute of Technology, 1201 E. California Boulevard, Pasadena, CA 91125, USA
³ Department of Molecular Oncology, Genentech, South San Francisco, CA94080, USA
⁴ Department of Neuroscience, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MA21205, USA

^* Author for correspondence (e-mail: wuwei{at}caltech.edu)

Accepted 23 December 2004

In developing limb skin, peripheral nerves are required for arterial differentiation, and guide the pattern of arterial branching. In vitro experiments suggest that nerve-derived VEGF may be important for arteriogenesis, but its role in vivo remains unclear. Using a series of nerve-specific Cre lines, we show that VEGF derived from sensory neurons, motoneurons and/or Schwann cells is required for arteriogenesis in vivo. Arteriogenesis also requires endothelial expression of NRP1, an artery-specific coreceptor for VEGF¹⁶⁴ that is itself induced by VEGF. Our results provide the first evidence that VEGF is necessary for arteriogenesis from a primitive capillary plexus in vivo, and show that in limb skin the nerve is indeed the principal source of this signal. They also suggest a model in which a `winner-takes-all' competition for VEGF may control arterial differentiation, with the outcome biased by a VEGF¹⁶⁴-NRP1 positive-feedback loop. Our results also demonstrate that nerve-vessel alignment is a necessary, but not sufficient, condition for nerve-induced arteriogenesis. Different mechanisms therefore probably underlie these endothelial patterning and differentiation processes.

Key words: VEGF, Neuropilin 1, Arterial differentiation, Mouse

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