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Published March 1, 2005 | Published + Supplemental Material
Journal Article Open

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


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 VEGF^(164) 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 VEGF^(164)-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.

Additional Information

© The Company of Biologists Ltd 2005. Accepted 23 December 2004. First published online 26 January 2005. We thank Andrew McMahon for Wnt1-Cre mice; Tom Jessell, Yasuto Tanabe and Chris William for Isl1-Cre mice; Alex Kolodkin and David Ginty for Nrp1lox/- mice and anti-NRP1 antibody; and T. Müller for providing anti-BFABP antibody. Thanks to R. Diamond, P. Koen and S. L. Adams for FACS assistance; S. Pease, B. Kennedy and the staff of the Transgenic Animal Facility at Caltech for assistance with mouse breeding and care; G. Mosconi for laboratory management; J. S. Chang and M. Martinez for technical support; and G. Mancuso for administrative assistance. Thanks also to D. H. Shin for invaluable help and discussion, C. Hochstim for helpful comments on the manuscript, and other Anderson lab members for technical help and discussion. D.J.A. is an Investigator of the Howard Hughes Medical Institute. Supplementary material for this article is available at http://dev.biologists.org/cgi/content/full/132/5/941/DC1

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