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Recombinant thrombomodulin domain 1 rescues pathological angiogenesis by inhibition of HIF-1α-VEGF pathway

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Abstract

Pathological angiogenesis (PA) contributes to various ocular diseases, including age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity, which are major causes of blindness over the world. Current treatments focus on anti-vascular endothelial growth factor (VEGF) therapy, but persistent avascular retina, recurrent intravitreal neovascularization, and general adverse effects are reported. We have previously found that recombinant thrombomodulin domain 1 (rTMD1) can suppress vascular inflammation. However, the function of rTMD1 in VEGF-induced PA remains unknown. In this study, we found that rTMD1 inhibited VEGF-induced angiogenesis in vitro. In an oxygen induced retinopathy (OIR) animal model, rTMD1 treatment significantly decreased retinal neovascularization but spared normal physiological vessel growth. Furthermore, loss of TMD1 significantly promoted PA in OIR. Meanwhile, hypoxia-inducible factor-1α, the transcription factor that upregulates VEGF, was suppressed after rTMD1 treatment. The levels of interleukin-6, and intercellular adhesion molecule-1 were also significantly suppressed. In conclusion, our results indicate that rTMD1 not only has dual effects to suppress PA and inflammation in OIR, but also can be a potential HIF-1α inhibitor for clinical use. These data bring forth the possibility of rTMD1 as a novel therapeutic agent for PA.

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Acknowledgements

Supported by Grants Ministry of Science and Technology 109-2628-B-006-032 to YHH and 110-2320-B-006-051 to HLW, Taiwan.

Funding

Supported by Grants Ministry of Science and Technology 109-2628-B-006-032 to YHH and 110-2320-B-006-051 to HLW, Taiwan.

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Authors and Affiliations

  1. Department of Ophthalmology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan

    Yi-Hsun Huang, I-Chen Peng, Yi-Sheng Chang & Sung-Huei Tseng

  2. International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan

    Cheng-Hsiang Kuo & Hua-Lin Wu

  3. Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada

    Edward M. Conway

  4. Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Hua-Lin Wu

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  1. Yi-Hsun Huang
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Contributions

YHH, ICP and HLW involved in design and conduct of study. Collection and management of the data were done by YHH, CHK and ICP. YHH, CHK, ICP, YSC, SHT, EMC and HLW participated in management and interpretation of the data. YHH, CHK, EMC and HLW participated in preparation, review, and approval of the manuscript.

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Correspondence to Yi-Hsun Huang or Hua-Lin Wu.

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All efforts were made to reduce both animal suffering and the number of animals used. All animal studies and procedures adhered to the Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision Research and were approved by the Institutional Animal Care and Use Committee at National Cheng Kung University.

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Huang, YH., Kuo, CH., Peng, IC. et al. Recombinant thrombomodulin domain 1 rescues pathological angiogenesis by inhibition of HIF-1α-VEGF pathway. Cell. Mol. Life Sci. 78, 7681–7692 (2021). https://doi.org/10.1007/s00018-021-03950-3

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  • DOI: https://doi.org/10.1007/s00018-021-03950-3

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