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

• Published in: eLife 2020-02, Vol.9
• Main Authors: Engelbrecht, Eric, Levesque, Michel V, He, Liqun, Vanlandewijck, Michael, Nitzsche, Anja, Niazi, Hira, Kuo, Andrew, Singh, Sasha A, Aikawa, Masanori, Holton, Kristina, Proia, Richard L, Kono, Mari, Pu, William T, Camerer, Eric, Betsholtz, Christer, Hla, Timothy
• Format: Article
• Language: English
• Subjects: Animals; Aorta; Aorta - metabolism; Arrestin; arterial endothelium; beta-Arrestins - metabolism; Biotechnology industries; Cardiology and cardiovascular system; Cellular Biology; Characterization; Chromatin; Chromosomes and Gene Expression; Coronary vessels; Endothelial cells; Endothelium; Endothelium, Lymphatic - metabolism; Endothelium, Vascular - metabolism; G protein-coupled receptors; G proteins; Gene expression; Genes; Glucocorticoids; Green Fluorescent Proteins - metabolism; Human health and pathology; Inflammation; Kinases; Life Sciences; lymphatic endothelium; Lysophospholipids - metabolism; Medical importance; Medicin och hälsovetenskap; Messenger RNA; Mice; Mice, Transgenic; NF-κB protein; Phosphates; Physiology; Proteins; Sequence Analysis, RNA - methods; Signal Transduction; Single-Cell Analysis - methods; Sphingosine; Sphingosine - analogs & derivatives; Sphingosine - metabolism; Sphingosine 1-phosphate; Sphingosine-1-Phosphate Receptors - genetics; Sphingosine-1-Phosphate Receptors - metabolism; Transcription; Transcriptome
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.52690

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.