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Transplant Toxicities

Thrombomodulin blocks calcineurin inhibitor-induced vascular permeability via inhibition of Src/VE-cadherin axis

Bone Marrow Transplantation volume 52, pages 245–251 (2017)Cite this article

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Abstract

Recombinant human soluble thrombomodulin (rTM) counteracted capillary leakage and alleviated edema in individuals with sinusoidal obstruction syndrome and engraftment syndrome after hematopoietic stem cell transplantation. We previously showed that rTM increased levels of antiapoptotic protein Mcl-1 and protected endothelial cells from calcineurin inhibitor cyclosporine A (CsA)-induced apoptosis. However, the molecular mechanisms by which rTM enhances barrier function in vascular endothelial cells remain unknown. Here we show that exposure of vascular endothelial EA.hy926 cells to CsA induced phosphorylation of Src/vascular endothelial cadherin (VE-cadherin) and translocation of VE-cadherin from cell surface to cytoplasm, resulting in an increase in vascular permeability. In addition, CsA increased production of inflammatory cytokines, including interleukin (IL)-1β and IL-6, associated with an increase in nuclear levels of nuclear factor-κB (NF-κB) which also enhanced vascular permeability. Importantly, the fourth and fifth regions of epidermal growth factor-like domain of TM (TME45) attenuated CsA-induced p-Src/VE-cadherin and vascular permeability in parallel with a decrease in nuclear levels of NF-κB and cytokine production in EA.hy926 cells. In conclusion, TM, especially TME45, maintains vascular integrity, at least in part, via Src signaling.

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Acknowledgements

This study was supported by grants from Uehara Memorial Foundation, SENSHIN Medical Research Foundation and KAKENHI (23591421 and 26461406).

Author contributions

TI contributed to the concept and design, interpreted and analyzed the data, and wrote the article; JY performed the experiments and wrote the article; CN performed the experiments; KU synthesized DHMEQ and critical revision; and AY provided important intellectual content and gave final approval.

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Author notes

  1. J Yang

    Present address: Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.,

Authors and Affiliations

  1. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi, Japan

    T Ikezoe, J Yang, C Nishioka & A Yokoyama

  2. Department of Hematology, Fukushima Medical University, Fukushima, Japan

    T Ikezoe

  3. Department of Molecular Target Medicine Screening, School of Medicine, Aichi Medical University, Aichi, Japan

    K Umezawa

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  1. T Ikezoe
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Correspondence to T Ikezoe.

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Ikezoe, T., Yang, J., Nishioka, C. et al. Thrombomodulin blocks calcineurin inhibitor-induced vascular permeability via inhibition of Src/VE-cadherin axis. Bone Marrow Transplant 52, 245–251 (2017). https://doi.org/10.1038/bmt.2016.241

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