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Therapeutic potential of pro-angiogenic BPC157 is associated with VEGFR2 activation and up-regulation

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Abstract

BPC 157, a pentadecapeptide with extensive healing effects, has recently been suggested to contribute to angiogenesis. However, the underlying mechanism is not yet clear. The present study aimed to explore the potential therapeutic effect and pro-angiogenic mechanism of BPC 157. As demonstrated by the chick chorioallantoic membrane (CAM) assay and endothelial tube formation assay, BPC 157 could increase the vessel density both in vivo and in vitro, respectively. BPC 157 could also accelerate the recovery of blood flow in the ischemic muscle of the rat hind limb as detected by laser Doppler scanning, indicating the promotion of angiogenesis. Histological analysis of the hind limb muscle confirmed the increased number of vessels and the enhanced vascular expression of vascular endothelial growth factor receptor 2 (VEGFR2) in rat with BPC 157 treatment. In vitro study using human vascular endothelial cells further confirmed the increased mRNA and protein expressions of VEGFR2 but not VEGF-A by BPC 157. In addition, BPC 157 could promote VEGFR2 internalization in vascular endothelial cells which was blocked in the presence of dynasore, an inhibitor of endocytosis. BPC 157 time dependently activated the VEGFR2-Akt-eNOS signaling pathway which could also be suppressed by dynasore. The increase of endothelial tube formation induced by BPC 157 was also inhibited by dynasore. This study demonstrates the pro-angiogenic effects of BPC 157 that is associated with the increased expression, internalization of VEGFR2, and the activation of VEGFR2-Akt-eNOS signaling pathway. BPC 157 promotes angiogenesis in CAM assay and tube formation assay. BPC 157 accelerates the blood flow recovery and vessel number in rats with hind limb ischemia. BPC 157 up-regulates VEGFR2 expression in rats with hind limb ischemia and endothelial cell culture. BPC 157 promotes VEGFR2 internalization in association with VEGFR2-Akt-eNOS activation.

Key message

  • BPC 157 promotes angiogenesis in CAM assay and tube formation assay.

  • BPC 157 accelerates the blood flow recovery and vessel number in rats with hind limb ischemia.

  • BPC 157 up-regulates VEGFR2 expression in rats with hind limb ischemia and endothelial cell culture.

  • BPC 157 promotes VEGFR2 internalization in association with VEGFR2-Akt-eNOS activation.

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Acknowledgments

This work was supported by the Chang Gung Memorial Hospital [Grants CMRPD1A0531, CMRPD1C0231, CMRPG391311, CMRPG3A1131] and the Ministry of Science and Technology, Taiwan [Grant NMRPD181001-3].

Author contributions

Authors responsible for concept and design were MJH, HTL, HYH, YL, and JHSP. Experimental performance: MJH, HTL, HYH, and YL. Technical supports: CNW, YSK, VHSC, and JSW. MJH, HTL, and JHSP were responsible in the analysis and interpretation of data. MJH and JHSP drafted the manuscript. MJH and HTL contribute to this work equally.

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Authors and Affiliations

  1. Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan City, Taiwan, Republic Of China

    Ming-Jer Hsieh, Hsien-Ta Liu, Hsiu-Yun Huang, Yuling Lin & Jong-Hwei S. Pang

  2. Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Lin-kou, Chang Gung University, Tao-Yuan City, Taiwan, Republic Of China

    Ming-Jer Hsieh & Yu-Shien Ko

  3. Division of Family Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan, Republic Of China

    Hsien-Ta Liu

  4. School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Hsien-Ta Liu

  5. Department of Obstetrics and Gynecology, Lin-Kou Medical Center, Chang Gung Memorial Hospital, Tao-Yuan City, Taiwan, Republic Of China

    Chao-Nin Wang

  6. Healthy Aging Research Center, Graduate Institute of Rehabilitation Science, Medical College, Chang Gung University, Tao-Yuan City, Taiwan, Republic Of China

    Jong-Shyan Wang

  7. Program for Translation Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, Republic Of China

    Vincent Hung-Shu Chang

  8. Department of Physical Medicine and Rehabilitation, Lin-Kou Medical Center, Chang Gung Memorial Hospital, Tao-Yuan City, Taiwan, Republic Of China

    Jong-Hwei S. Pang

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  1. Ming-Jer Hsieh
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  9. Jong-Hwei S. Pang
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Correspondence to Jong-Hwei S. Pang.

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All procedures complied with the standards for care and use of animal subjects as stated in the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Resources, National Academy of Sciences, Bethesda, MD). The protocols in our animal studies were approved by the Institutional Animal Care and Use Committee of Chang Gung University.

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The authors declare that they have no competing interests.

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Hsieh, MJ., Liu, HT., Wang, CN. et al. Therapeutic potential of pro-angiogenic BPC157 is associated with VEGFR2 activation and up-regulation. J Mol Med 95, 323–333 (2017). https://doi.org/10.1007/s00109-016-1488-y

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  • DOI: https://doi.org/10.1007/s00109-016-1488-y

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