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Journal of Molecular Medicine

, Volume 95, Issue 3, pp 323–333 | Cite as

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

  • Ming-Jer Hsieh
  • Hsien-Ta Liu
  • Chao-Nin Wang
  • Hsiu-Yun Huang
  • Yuling Lin
  • Yu-Shien Ko
  • Jong-Shyan Wang
  • Vincent Hung-Shu Chang
  • Jong-Hwei S. PangEmail author
Original Article

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.

Keywords

BPC 157 Angiogenesis CAM assay Tube formation Hind limb ischemia VEGFR2 

Notes

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.

Compliance with ethical standards

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.

Conflict of interest

The authors declare that they have no competing interests.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Ming-Jer Hsieh
    • 1
    • 2
  • Hsien-Ta Liu
    • 1
    • 3
    • 4
  • Chao-Nin Wang
    • 5
  • Hsiu-Yun Huang
    • 1
  • Yuling Lin
    • 1
  • Yu-Shien Ko
    • 2
  • Jong-Shyan Wang
    • 6
  • Vincent Hung-Shu Chang
    • 7
  • Jong-Hwei S. Pang
    • 1
    • 8
    Email author
  1. 1.Graduate Institute of Clinical Medical Sciences, College of MedicineChang Gung UniversityTao-Yuan CityRepublic Of China
  2. 2.Division of Cardiology, Department of Internal MedicineChang Gung Memorial Hospital-Lin-kou, Chang Gung UniversityTao-Yuan CityRepublic Of China
  3. 3.Division of Family MedicineShuang Ho Hospital, Taipei Medical UniversityTaipeiRepublic Of China
  4. 4.School of Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
  5. 5.Department of Obstetrics and Gynecology, Lin-Kou Medical CenterChang Gung Memorial HospitalTao-Yuan CityRepublic Of China
  6. 6.Healthy Aging Research Center, Graduate Institute of Rehabilitation Science, Medical CollegeChang Gung UniversityTao-Yuan CityRepublic Of China
  7. 7.Program for Translation Medicine, College of Medical Science and TechnologyTaipei Medical UniversityTaipeiRepublic Of China
  8. 8.Department of Physical Medicine and Rehabilitation, Lin-Kou Medical CenterChang Gung Memorial HospitalTao-Yuan CityRepublic Of China

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