Journal
DEVELOPMENTAL CELL
Volume 24, Issue 4, Pages 359-371Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2013.01.009
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Funding
- National Heart, Lung, and Blood Institute, National Institutes of Health
- Grants-in-Aid for Scientific Research [24111003, 24111001, 22390096] Funding Source: KAKEN
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In developing limb skin, peripheral nerves provide a spatial template that controls the branching pattern and differentiation of arteries. Our previous studies indicate that nerve-derived VEGF-A is required for arterial differentiation but not for nerve-vessel alignment. In this study, we demonstrate that nerve-vessel alignment depends on the activity of Cxcl12-Cxcr4 chemokine signaling. Genetic inactivation of Cxcl12-Cxcr4 signaling perturbs nerve-vessel alignment and abolishes arteriogenesis. Further in vitro assays allow us to uncouple nerve-vessel alignment and arteriogenesis, revealing that nerve-derived Cxcl12 stimulates endothelial cell migration, whereas nerve-derived VEGF-A is responsible for arterial differentiation. These findings suggest a coordinated sequential action in which nerve Cxcl12 functions over a distance to recruit vessels to align with nerves, and subsequent arterial differentiation presumably requires a local action of nerve VEGF-A in the nerve-associated vessels.
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