Hypoxia-mediated induction of CXCL12 and VEGF-A in sensory nerves determines the pattern of arterial differentiation and vascular branching morphogenesis in the skin

Authors

• WL Li
• A Sajja
• YS Mukouyama

Abstract

During vascular development, a primary capillary network undergoes intensive vascular remodeling and develops into a hierarchical vascular branching network. In these processes, organ-specific local signals coordinate tissues-specific vascular branching pattern and differentiation. We have previously demonstrated that in the embryonic skin, sensory nerve-derived signals such as CXCL12 and VEGF-A coordinate the vascular branching pattern and arterial differentiation. Here we seek to understand what specifies the correct timing of these angiogenic signals in order to form the stereotypical branching pattern of the neuro-vascular network. Our initial studies have revealed that oxygen-starved sensory nerves may trigger CXCL12 and VEGF-A expression. By using a hypoxia imaging agent, we have determined areas of local hypoxia prior to nerve-vessel alignment. Furthermore, we have characterized the complex timing mechanism of CXCL12 and VEGF-A induction in response to hypoxia in the dissociated dorsal root ganglia culture containing sensory neurons and glia. These data suggest two distinct transcriptional mechanisms underlying the expression of the hypoxia-induced CXCL12 and VEGF-A in the nerve. We are currently examining whether HIF and FOXC families of transcription factor regulate these expression to control nerve-vessel alignment and arterial differentiation in the skin. Our preliminary data suggest the important role of HIFs on arterial differentiation but not on vascular branching along with the nerves. These experiments have been critical in shedding light on regulatory mechanisms of branching morphogenesis and patterning by the metabolic microenvironment during development.

Scientific Focus Area: Developmental Biology

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