Journal
DEVELOPMENTAL CELL
Volume 52, Issue 6, Pages 779-+Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2020.01.016
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Funding
- NIH [R35 HL135821, EY017017, 1U54HD090255, R24 EY024864]
- Fondation Leducq transatlantic network grant (SphingoNet)
- Swedish Cancer Foundation
- American Heart Association
- Japan Society for the Promotion of Science Overseas Research Fellowships
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Transcriptional mechanisms that drive angiogenesis and organotypic vascular endothelial cell specialization are poorly understood. Here, we show that retinal endothelial sphingosine 1-phosphate receptors (S1PRs), which restrain vascular endothelial growth factor (VEGF)-induced angiogenesis, spatially restrict expression of JunB, a member of the activator protein 1 (AP-1) family of transcription factors (TFs). Mechanistically, VEGF induces JunB expression at the sprouting vascular front while S1PR-dependent vascular endothelial (VE)-cadherin assembly suppresses JunB expression in the nascent vascular network, thus creating a gradient of this TF. Endothelial-specific JunB knockout mice showed diminished expression of neurovascular guidance genes and attenuated retinal vascular network progression. In addition, endothelial S1PR signaling is required for normal expression of b-catenin-dependent genes such as TCF/LEF1 and ZIC3 TFs, transporters, and junctional proteins. These results show that S1PR signaling restricts JunB function to the expanding vascular front, thus creating an AP-1 gradient and enabling organotypic endothelial cell specialization of the vascular network.
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