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

Engelbrecht, E.; Levesque, M. V.; He, L.; Vanlandewijck, M.; Nitzsche, A.; Kuo, A.; Singh, S. A.; Aikawa, M.; Holton, K.; Proia, R. L.; Kono, M.; Pu, W. T.; Camerer, E.; Betsholtz, C.; Hla, T.

doi:10.1101/802892

bioRxiv · 10.1101/802892

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

Engelbrecht, E.·Levesque, M. V.·He, L.·Vanlandewijck, M.·Nitzsche, A.·Kuo, A.·Singh, S. A.·Aikawa, M.·Holton, K.·Proia, R. L.·Kono, M.·Pu, W. T.·Camerer, E.·Betsholtz, C.·Hla, T.

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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, spatially distinct S1PR1 signaling in the aorta is associated with heterogenous endothelial cell (EC) subtypes. For example, a transcriptomically distinct arterial EC population at vascular branch points (aEC1) exhibits ligand- independent S1PR1/{beta}-arrestin coupling. In contrast, circulatory S1P-dependent S1PR1/{beta}-arrestin coupling was observed in non-branch point aEC2 cells that exhibit an inflammatory signature. Moreover, an adventitial lymphatic EC (LEC) population shows suppression of lymphangiogenic and inflammation-related transcripts in a S1P/S1PR1-dependent manner. These insights add resolution to existing concepts of GPCR signaling and S1P biology.

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Engelbrecht, E., Levesque, M. V., He, L., Vanlandewijck, M., Nitzsche, A., Kuo, A., Singh, S. A., Aikawa, M., Holton, K., Proia, R. L., Kono, M., Pu, W. T., Camerer, E., Betsholtz, C., Hla, T.. 2019-10-13. Sphingosine 1-phosphate-regulated transcriptomes in heterogenous arterial and lymphatic endothelium of the aorta. https://doi.org/10.1101/802892

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