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Profiling of Vascular Reparative Signaling using Sphingosine‐1‐Phospate Receptor 1 Reporter Mice
Author(s) -
Akhter Md Zahid,
Joshi Jagdish C.,
BR Vijay Avin,
Mehta Dolly
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03740
Subject(s) - s1pr1 , sphingosine , microbiology and biotechnology , downregulation and upregulation , cd31 , biology , transplantation , endothelial stem cell , stat3 , immunology , cancer research , angiogenesis , signal transduction , chemistry , receptor , vascular endothelial growth factor a , medicine , vascular endothelial growth factor , in vitro , biochemistry , gene , vegf receptors
Loss of endothelial barrier function is a hall mark of acute lung injury, which induces 40% lethality in affected patients. Sphingosine‐1‐phosphate receptor 1 (S1PR1) upon ligating S1P on endothelial cell (EC) surface enhances endothelial barrier function and reverses lung vascular hyper‐permeability in a variety of inflammatory injury including endotoxin, LPS. Whether S1PR1 is activated dynamically following lung injury in ECs and repairs barrier exclusively through EC‐cell surface signaling remains enigmatic. Using S1PR1‐GFP‐signaling reporter mice (S1PR1 reporter) mice, in which nuclear GFP reports for S1PR1 activity, along with FACS and bone marrow transplantation approaches, we show that LPS primarily activates S1PR1 in resident ECs (CD45 − CD31 + GFP + ) which reached its maximal level at 16 h. Intriguingly, S1PR1‐actived ECs showed enhanced proliferation in vivo and in vitro . RNA seq analysis of sorted GFP‐S1PR1‐ECs identified the transcription factor EGR1 , SPHK1 and SPNS2 as top 100 hundred genes. We show that S1PR1 induced EGR1 expression which in turn upregulated SPHK1 expression. We also found that S1PR1 induced SPNS2 through STAT3. Upregulated SPHK1 and SPNS2 lead to amplification of S1P generation and transport. Thus, transplantation of GFP‐S1PR1‐ECs in matrigel induced vascularization and these ECs also repaired defective vascular barrier in lungs of mice conditionally lacking EC‐S1PR1. Findings show that S1PR1 induces self‐driven reparative transcriptional signaling for endothelial barrier repair.