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Hyperoxia-induced S1P1 signaling reduced angiogenesis by suppression of TIE-2 leading to experimental bronchopulmonary dysplasia

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Abstract

Introduction

We have earlier shown that hyperoxia (HO)-induced sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) signaling contribute to bronchopulmonary dysplasia (BPD). S1P acts through G protein-coupled receptors, S1P1 through S1P5. Further, we noted that heterozygous deletion of S1pr1 ameliorated the HO-induced BPD in the murine model. The mechanism by which S1P1 signaling contributes to HO-induced BPD was explored.

Methods

S1pr1+/+ and S1pr1+/− mice pups were exposed to either room air (RA) or HO (75% oxygen) for 7 days from PN 1–7. Lung injury and alveolar simplification was evaluated. Lung protein expression was determined by Western blotting and immunohistochemistry (IHC). In vitro experiments were performed using human lung microvascular endothelial cells (HLMVECs) with S1P1 inhibitor, NIBR0213 to interrogate the S1P1 signaling pathway.

Results

HO increased the expression of S1pr1 gene as well as S1P1 protein in both neonatal lungs and HLMVECs. The S1pr1+/− neonatal mice showed significant protection against HO-induced BPD which was accompanied by reduced inflammation markers in the bronchoalveolar lavage fluid. HO-induced reduction in ANG-1, TIE-2, and VEGF was rescued in S1pr1+/− mouse, accompanied by an improvement in the number of arterioles in the lung. HLMVECs exposed to HO increased the expression of KLF-2 accompanied by reduced expression of TIE-2, which was reversed with S1P1 inhibition.

Conclusion

HO induces S1P1 followed by reduced expression of angiogenic factors. Reduction of S1P1 signaling restores ANG-1/ TIE-2 signaling leading to improved angiogenesis and alveolarization thus protecting against HO-induced neonatal lung injury.

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Acknowledgements

We gratefully acknowledge the assistance of Research Resources Center histology core of University of Illinois, Chicago, and that of University of Chicago in the processing of lung tissue, including IHC and image processing. We have used biorender.com to create the illustrations.

Funding

This work was supported in part by R01HD090887-01A1 from Eunice Kennedy Shriver National Institute of Child Health and Human Development and by Transitional Grant # 18TPA34230095 from American Heart Association to AH. No role was played by the funding body in the design of the study, collection, analysis and interpretation of data, or in writing the manuscript.

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Authors and Affiliations

  1. Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA

    Tara Sudhadevi, Alison W. Ha, Prathima Basa, Jaya M. Thomas & Anantha Harijith

  2. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA

    Anjum Jafri

  3. Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Panfeng Fu, Kishore Wary, Dolly Mehta & Viswanathan Natarajan

  4. Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Viswanathan Natarajan

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  1. Tara Sudhadevi
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Correspondence to Anantha Harijith.

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Sudhadevi, T., Jafri, A., Ha, A.W. et al. Hyperoxia-induced S1P1 signaling reduced angiogenesis by suppression of TIE-2 leading to experimental bronchopulmonary dysplasia. Cell Biochem Biophys 79, 561–573 (2021). https://doi.org/10.1007/s12013-021-01014-8

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