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Sphingosine 1-phosphate-regulated transcriptomes in heterogenous arterial and lymphatic endothelium of the aorta.

  • Engelbrecht, Eric1
  • Levesque, Michel V1
  • He, Liqun2, 3
  • Vanlandewijck, Michael2, 3
  • Nitzsche, Anja4
  • Niazi, Hira4
  • Kuo, Andrew1
  • Singh, Sasha A5
  • Aikawa, Masanori5
  • Holton, Kristina6
  • Proia, Richard L7
  • Kono, Mari7
  • Pu, William T8, 9
  • Camerer, Eric4
  • Betsholtz, Christer2, 3
  • Hla, Timothy1
  • 1 Vascular Biology Program, Boston Children's Hospital, Deapartment of Surgery, Harvard Medical School, Boston, United States. , (United States)
  • 2 Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden. , (Sweden)
  • 3 Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Karolinska Institutet, Huddinge, Sweden. , (Sweden)
  • 4 Université de Paris, INSERM U970, Paris Cardiovascular Research Center, Paris, France. , (France)
  • 5 Center for Interdisciplinary Cardiovascular Sciences, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States. , (United States)
  • 6 Harvard Medical School Research Computing, Boston, United States. , (United States)
  • 7 Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States. , (United States)
  • 8 Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, United States. , (United States)
  • 9 Harvard Stem Cell Institute, Harvard University, Cambridge, United States. , (United States)
Published Article
"eLife Sciences Organisation, Ltd."
Publication Date
Feb 24, 2020
DOI: 10.7554/eLife.52690
PMID: 32091396


Despite the medical importance of G protein-coupled receptors (GPCRs), in vivo cellular heterogeneity of GPCR signaling and downstream transcriptional responses are not understood. We report the comprehensive characterization of transcriptomes (bulk and single-cell) and chromatin domains regulated by sphingosine 1-phosphate receptor-1 (S1PR1) in adult mouse aortic endothelial cells. First, S1PR1 regulates NFκB and nuclear glucocorticoid receptor pathways to suppress inflammation-related mRNAs. Second, S1PR1 signaling in the heterogenous endothelial cell (EC) subtypes occurs at spatially-distinct areas of the aorta. For example, a transcriptomically distinct arterial EC population at vascular branch points (aEC1) exhibits ligand-independent S1PR1/ß-arrestin coupling. In contrast, circulatory S1P-dependent S1PR1/ß-arrestin coupling was observed in non-branch point aEC2 cells that exhibit an inflammatory gene expression signature. Moreover, S1P/S1PR1 signaling regulates the expression of lymphangiogenic and inflammation-related transcripts in an adventitial lymphatic EC (LEC) population in a ligand-dependent manner. These insights add resolution to existing concepts of endothelial heterogeneity, GPCR signaling and S1P biology.

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