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Development ePress online publication date 26 Jan 2005
doi: 10.1242/dev.01675

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Research article

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


Yoh-suke Mukouyama, Hans-Peter Gerber, Napoleone Ferrara, Chenghua Gu, and David J. Anderson*
* Author for correspondence (e-mail: wuwei{at}caltech.edu)

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 co-receptor 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.
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