Skip to main content
SpringerLink
Log in

Comparison of Angiogenic Activities of Three Neuropeptides, Substance P, Secretoneurin, and Neuropeptide Y Using Myocardial Infarction

  • Original Article
  • Published:
Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

BACKGROUND:

The interplay between neurogenesis and angiogenesis is crucial during the development mediated by neuro-angiogenic morphogens. In particular, the angiogenic activity of neuropeptides and their role in tissue regeneration have long been investigated for better understanding of their biological mechanisms and further applications. However, there have been few studies for direct comparison of angiogenic activities of neuropeptides for in vitro and in vivo models. In this study, we report that direct comparison of the angiogenic activities of neuropeptide Y, secretoneurin, and substance P (SP) immobilized on hydrogels in in vitro and in vivo experiments.

METHODS:

A hyaluronic acid-based hydrogel is prepared by utilizing acrylated hyaluronic acid and thiolated peptides as a crosslinker and angiogenic factors, respectively. Angiogenic activities of three neuropeptides are evaluated not only by in vitro angiogenic and gene expression assays, but also by an in vivo chronic myocardial infarction model.

RESULTS:

The comparison of in vitro angiogenic activities of three peptides demonstrates that the SP-immobilized hydrogel shows a higher degree of cell network formation and angiogenic-specific genes than those of the other peptides and the control case. In addition, a three-dimensional angiogenic assay illustrates that more sprouting is observable in the SP group. Evaluation of regenerative activity in the chronic myocardial infarction model reveals that all three peptide-immobilized hydrogels induce increased cardiac function as well as structural regeneration. Among all the cases, the SP group provided the highest regenerative activity both in vitro and in vivo.

CONCLUSION:

In our comparison study, the SP-immobilized hydrogel shows the highest angiogenic activity and tissue regeneration among the test groups. This result suggests that nerve regeneration factors help angiogenesis in damaged tissues, which also highlights the importance of the neuro-angiogenic peptides as an element of tissue regeneration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Rouwkema J, Khademhosseini A. Vascularization and angiogenesis in tissue engineering: beyond creating static networks. Trends Biotechnol. 2016;34:733–45.

    Article  PubMed  CAS  Google Scholar 

  2. Zachary I, Morgan RD. Therapeutic angiogenesis for cardiovascular disease: biological context, challenges, prospects. Heart. 2011;97:181–9.

    Article  PubMed  CAS  Google Scholar 

  3. Goncalves LM. Angiogenic growth factors: potential new treatment for acute myocardial infarction? Cardiovasc Res. 2000;45:294–302.

    Article  PubMed  CAS  Google Scholar 

  4. Testa U, Pannitteri G, Condorelli GL. Vascular endothelial growth factors in cardiovascular medicine. J Cardiovasc Med. 2008;9:1190–221.

    Article  Google Scholar 

  5. Jain M, LoGerfo FW, Guthrie P, Pradhan L. Effect of hyperglycemia and neuropeptides on interleukin-8 expression and angiogenesis in dermal microvascular endothelial cells. J Vasc Surg. 2011;53:1654–60.

    Article  PubMed  Google Scholar 

  6. Lee EW, Michalkiewicz M, Kitlinska J, Kalezic I, Switalska H, Yoo P, et al. Neuropeptide Y induces ischemic angiogenesis and restores function of ischemic skeletal muscles. J Clin Invest. 2003;111:1853–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Kim JH, Jung Y, Kim BS, Kim SH. Stem cell recruitment and angiogenesis of neuropeptide substance P coupled with self-assembling peptide nanofiber in a mouse hind limb ischemia model. Biomaterials. 2013;34:1657–68.

    Article  PubMed  CAS  Google Scholar 

  8. Lv T, Liang W, Li L, Cui X, Wei X, Pan H, et al. Novel calcitonin gene-related peptide/chitosan-strontium-calcium phosphate cement: enhanced proliferation of human umbilical vein endothelial cells in vitro. J Biomed Mater Res B Appl Biomater. 2018. https://doi.org/10.1002/jbm.b.34091.

    Article  PubMed  Google Scholar 

  9. Yang J, Shi QD, Song TB, Feng GF, Zang WJ, Zong CH, et al. Vasoactive intestinal peptide increases VEGF expression to promote proliferation of brain vascular endothelial cells via the cAMP/PKA pathway after ischemic insult in vitro. Peptides. 2013;42:105–11.

    Article  PubMed  CAS  Google Scholar 

  10. Fischer-Colbrie R, Kirchmair R, Kahler CM, Wiedermann CJ, Saria A. Secretoneurin: a new player in angiogenesis and chemotaxis linking nerves, blood vessels and the immune system. Curr Protein Pept Sci. 2005;6:373–85.

    Article  PubMed  CAS  Google Scholar 

  11. Theurl M, Schgoer W, Albrecht K, Jeschke J, Egger M, Beer AG, et al. The neuropeptide catestatin acts as a novel angiogenic cytokine via a basic fibroblast growth factor-dependent mechanism. Circ Res. 2010;107:1326–35.

    Article  PubMed  CAS  Google Scholar 

  12. Albrecht-Schgoer K, Schgoer W, Holfeld J, Theurl M, Wiedemann D, Steger C, et al. The angiogenic factor secretoneurin induces coronary angiogenesis in a model of myocardial infarction by stimulation of vascular endothelial growth factor signaling in endothelial cells. Circulation. 2012;126:2491–501.

    Article  PubMed  CAS  Google Scholar 

  13. Ekstrand AJ, Cao R, Bjorndahl M, Nystrom S, Jonsson-Rylander AC, Hassani H, et al. Deletion of neuropeptide Y (NPY) 2 receptor in mice results in blockage of NPY-induced angiogenesis and delayed wound healing. Proc Natl Acad Sci USA. 2003;100:6033–8.

    Article  PubMed  CAS  Google Scholar 

  14. Kohara H, Tajima S, Yamamoto M, Tabata Y. Angiogenesis induced by controlled release of neuropeptide substance P. Biomaterials. 2010;31:8617–25.

    Article  PubMed  CAS  Google Scholar 

  15. Simon-Yarza T, Formiga FR, Tamayo E, Pelacho B, Prosper F, Blanco-Prieto MJ. Vascular endothelial growth factor-delivery systems for cardiac repair: an overview. Theranostics. 2012;2:541–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Silva EA, Mooney DJ. Spatiotemporal control of vascular endothelial growth factor delivery from injectable hydrogels enhances angiogenesis. J Thromb Haemost. 2007;5:590–8.

    Article  PubMed  CAS  Google Scholar 

  17. Song M, Jang H, Lee J, Kim JH, Kim SH, Sun K, et al. Regeneration of chronic myocardial infarction by injectable hydrogels containing stem cell homing factor SDF-1 and angiogenic peptide Ac-SDKP. Biomaterials. 2014;35:2436–45.

    Article  PubMed  CAS  Google Scholar 

  18. Kim J, Kim IS, Cho TH, Lee KB, Hwang SJ, Tae G, et al. Bone regeneration using hyaluronic acid-based hydrogel with bone morphogenic protein-2 and human mesenchymal stem cells. Biomaterials. 2007;28:1830–7.

    Article  PubMed  CAS  Google Scholar 

  19. Kim J, Kim IS, Cho TH, Kim HC, Yoon SJ, Choi J, et al. In vivo evaluation of MMP sensitive high-molecular weight HA-based hydrogels for bone tissue engineering. J Biomed Mater Res A. 2010;95:673–81.

    Article  PubMed  CAS  Google Scholar 

  20. Del Duca D, Werbowetski T, Del Maestro RF. Spheroid preparation from hanging drops: characterization of a model of brain tumor invasion. J Neurooncol. 2004;67:295–303.

    Article  PubMed  Google Scholar 

  21. Xiong Y, Mahmood A, Chopp M. Angiogenesis, neurogenesis and brain recovery of function following injury. Curr Opin Investig Drugs. 2010;11:298–308.

    PubMed  PubMed Central  CAS  Google Scholar 

  22. James JM, Mukouyama YS. Neuronal action on the developing blood vessel pattern. Semin Cell Dev Biol. 2011;22:1019–27.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zhang JH, Badaut J, Tang J, Obenaus A, Hartman R, Pearce WJ. The vascular neural network–a new paradigm in stroke pathophysiology. Nat Rev Neurol. 2012;8:711–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Albrecht-Schgoer K, Barthelmes J, Schgoer W, Theurl M, Nardin I, Lener D, et al. Nanoparticular delivery system for a secretoneurin derivative induces angiogenesis in a hind limb ischemia model. J Control Release. 2017;250:1–8.

    Article  PubMed  CAS  Google Scholar 

  25. Tilan JU, Everhart LM, Abe K, Kuo-Bonde L, Chalothorn D, Kitlinska J, et al. Platelet neuropeptide Y is critical for ischemic revascularization in mice. FASEB J. 2013;27:2244–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Um JH, Yu JY, Cubon MJ, Park KS. Substance P and Thiorphan synergically enhance angiogenesis in wound healing. Tissue Eng Regen Med. 2016;13:149–54.

    Article  CAS  Google Scholar 

  27. Wang Y, Zhang D, Ashraf M, Zhao T, Huang W, Ashraf A, et al. Combining neuropeptide Y and mesenchymal stem cells reverses remodeling after myocardial infarction. Am J Physiol Heart Circ Physiol. 2010;298:H275–86.

    Article  PubMed  CAS  Google Scholar 

  28. Kim J, Park Y, Tae G, Lee KB, Hwang SJ, Kim IS, et al. Synthesis and characterization of matrix metalloprotease sensitive-low molecular weight hyaluronic acid based hydrogels. J Mater Sci Mater Med. 2008;19:3311–8.

    Article  PubMed  CAS  Google Scholar 

  29. Ejaz A, LoGerfo FW, Khabbaz K, Pradhan L. Expression of neuropeptide Y, substance P, and their receptors in the right atrium of diabetic patients. Clin Transl Sci. 2011;4:346–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Yoon SJ, Hong S, Fang YH, Song M, Son KH, Son HS, et al. Differential regeneration of myocardial infarction depending on the progression of disease and the composition of biomimetic hydrogel. J Biosci Bioeng. 2014;118:461–8.

    Article  PubMed  CAS  Google Scholar 

  31. Mistrova E, Kruzliak P, Chottova Dvorakova M. Role of substance P in the cardiovascular system. Neuropeptides. 2016;58:41–51.

    Article  PubMed  CAS  Google Scholar 

  32. Wang J, Conboy I. Embryonic versus adult myogenesis: challenging the ‘regeneration recapitulates development’paradigm. J Mol Cell Biol. 2009;2:1–4.

    Article  PubMed  CAS  Google Scholar 

  33. Bonner-Weir S, Baxter LA, Schuppin GT, Smith FE. A second pathway for regeneration of adult exocrine and endocrine pancreas: a possible recapitulation of embryonic development. Diabetes. 1993;42:1715–20.

    Article  PubMed  CAS  Google Scholar 

  34. Imokawa Y, Yoshizato K. Expression of Sonic hedgehog gene in regenerating newt limb blastemas recapitulates that in developing limb buds. 1. Rouwkema J, Khademhosseini A. Vascularization and angiogenesis in tissue engineering: beyond creating static networks. Trends Biotechnol. 2016;34:733–45.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the grant from the National Research Foundation of Korea, Republic of Korea (Grant No. 2016-M3A9B6947892) and a Korea University Grant.

Author information

Author notes

    Authors and Affiliations

    1. Department of Biomedical Engineering, College of Medicine, Korea University, 73 Inchon-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea

      Jaeyeon Lee, Myeongjin Song, Jongseong Kim & Yongdoo Park

    Authors
    1. Jaeyeon Lee
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Myeongjin Song
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Jongseong Kim
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yongdoo Park
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Jongseong Kim or Yongdoo Park.

    Ethics declarations

    Conflict of interest

    The authors have no financial conflicts of interest.

    Ethical statement

    The animal experiment procedures were approved by the institutional animal care and use committee of Korea University College of Medicine (KUIACUC-2015-165).

    Additional information

    Jaeyeon Lee and Myeongjin Song equally contributed to this paper.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Lee, J., Song, M., Kim, J. et al. Comparison of Angiogenic Activities of Three Neuropeptides, Substance P, Secretoneurin, and Neuropeptide Y Using Myocardial Infarction. Tissue Eng Regen Med 15, 493–502 (2018). https://doi.org/10.1007/s13770-018-0134-x

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s13770-018-0134-x

    Keywords

    Search

    Navigation