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.
Mukouyama
Yoh-Suke
YS
Division of Biology 216-76, California Institute of Technology, 1201 E. California Boulevard, Pasadena, CA 91125, USA.
Gerber
Hans-Peter
HP
Ferrara
Napoleone
N
Gu
Chenghua
C
Anderson
David J
DJ
D000818:Animals; D001158:Arteries / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D005434:Flow Cytometry; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D039942:Neuropilin-1 / Q000378:metabolism*; D010525:Peripheral Nerves / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms; D045522:Recombinases / Q000378:metabolism; D011995:Recombination, Genetic; D012583:Schwann Cells / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D020033:Protein Isoforms; D045522:Recombinases; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1