Sphingosine 1-phosphate-regulated transcriptomes in heterogenous arterial and lymphatic endothelium of the aorta
- Harvard Medical School, United States
- Uppsala University, Sweden
- Université de Paris, INSERM U970, Paris Cardiovascular Research Center, France
- Brigham and Women's Hospital, Harvard Medical School, United States
- Harvard Medical School Research Computing, United States
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, United States
- Boston Children's Hospital, Harvard Medical School, United States
Abstract
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 NFkB 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/β-arrestin coupling. In contrast, circulatory S1P-dependent S1PR1/β-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 GPCR signaling and S1P biology.
Data availability
Sequencing data and processed files have been deposited in GEO under the accession GSE139065.
Article and author information
Author details
Funding
National Heart, Lung, and Blood Institute (R35 HL135821)
- Timothy Hla
Fondation Leducq (SphingoNet Transatlantic Network Grant)
- Richard L Proia
- Eric Camerer
- Christer Betsholtz
- Timothy Hla
National Institute of Diabetes and Digestive and Kidney Diseases (Intramural program support)
- Richard L Proia
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#16-10-3297) of the Boston Children's Hospital. All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Sphingosine 1-phosphate-regulated transcriptomes in heterogenous arterial and lymphatic endothelium of the aorta
eLife 9:e52690.
https://doi.org/10.7554/eLife.52690
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