Sphingosine 1-Phosphate Receptor Signaling Establishes AP-1 Gradients to Allow for Retinal Endothelial Cell Specialization.

Autor:	Yanagida K; Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, USA., Engelbrecht E; Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, USA., Niaudet C; Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, USA., Jung B; Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, USA., Gaengel K; Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden., Holton K; Harvard Medical School Research Computing, Boston, MA, USA., Swendeman S; Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, USA., Liu CH; Department of Medicine, Weill Cornell Medicine, New York, NY, USA., Levesque MV; Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, USA., Kuo A; Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, USA., Fu Z; Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Smith LEH; Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Betsholtz C; Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; ICMC (Integrated Cardio Metabolic Centre), Karolinska Institutet, Novum, Huddinge, Sweden., Hla T; Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: timothy.hla@childrens.harvard.edu.
Jazyk:	angličtina
Zdroj:	Developmental cell [Dev Cell] 2020 Mar 23; Vol. 52 (6), pp. 779-793.e7. Date of Electronic Publication: 2020 Feb 13.
DOI:	10.1016/j.devcel.2020.01.016
Abstrakt:	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 β-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. Competing Interests: Declaration of Interests The authors declare no competing interests. (Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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