Peripheral Nerve-Derived CXCL12 and VEGF-A Regulate the Patterning of Arterial Vessel Branching in Developing Limb Skin

• DOI: 10.1016/j.devcel.2013.01.009
• Publication Date: 2013-02-07T16:45:30Z
• Authors: Wenling Li; Hiroshi Kohara; Yutaka Uchida; Jennifer M. James; Kosha Soneji; Darran G. Cronshaw; Yong-Rui Zou; Takashi Nagasawa; Yoh-suke Mukouyama
• Keywords: Mice, Knockout; 0301 basic medicine; Receptors, CXCR4; Integrases; Reverse Transcriptase Polymerase Chain Reaction; Blotting, Western; Cell Differentiation; Extremities; Arteries; Flow Cytometry; Real-Time Polymerase Chain Reaction; Chemokine CXCL12; Mice; 03 medical and health sciences; Cell Movement; Ganglia, Spinal; Animals; Endothelium, Vascular; RNA, Messenger; Cells, Cultured; In Situ Hybridization; Developmental Biology; Skin

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.