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Angiogenesis

, Volume 21, Issue 3, pp 653–665 | Cite as

Angio-3, a 10-residue peptide derived from human plasminogen kringle 3, suppresses tumor growth in mice via impeding both angiogenesis and vascular permeability

  • Shruthi Venugopal
  • Chieh Kao
  • Ritu Chandna
  • Konerirajapuram N. Sulochana
  • Vivekanandan Subramanian
  • Mo Chen
  • R. Manjunatha Kini
  • Ruowen Ge
Original Paper

Abstract

Anti-angiogenesis therapy is an established therapeutic strategy for cancer. The endogenous angiogenic inhibitor angiostatin contains the first 3–4 kringle domains of plasminogen and inhibits both angiogenesis and vascular permeability. We present here a 10-residue peptide, Angio-3, derived from plasminogen kringle 3, which retains the functions of angiostatin in inhibiting both angiogenesis and vascular permeability. NMR studies indicate that Angio-3 holds a solution structure similar to the corresponding region of kringle 3. Mechanistically, Angio-3 inhibited both VEGF- and bFGF-induced angiogenesis by inhibiting EC proliferation and migration while inducing apoptosis. Inhibition of VEGF-induced vascular permeability results from its ability to impede VEGF-induced dissociation of adherens junction and tight junction proteins as well as the formation of actin stress fibers. When administered intravenously, Angio-3 inhibited subcutaneous breast cancer and melanoma growth by suppressing both tumor angiogenesis and intra-tumor vascular permeability. Hence, Angio-3 is a novel dual inhibitor of angiogenesis and vascular permeability. It is valuable as a lead peptide that can be further developed as therapeutics for diseases involving excessive angiogenesis and/or vascular permeability.

Keywords

Angiogenesis Vascular permeability Kringle domain Peptide Plasminogen 

Abbreviations

EC

Endothelial cell

VEGF

Vascular endothelial growth factor

NMR

Nuclear magnetic resonance

K5

Kringle 5

VP

Vascular permeability

HUVECs

Human umbilical vein endothelial cells

HMVECs

Human dermal microvascular endothelial cells

HRECs

Human retinal endothelial cells

bFGF

Basic fibroblast growth factor

Notes

Acknowledgements

This work is supported by research grants from Singapore Ministry of Education (RP950358 and RP981308) and Singapore National Medical Research Council (CBRG13nov061) to RG.

Author contributions

RG supervised the research; RMK designed the peptide; SV performed most of the experiments with contributions from CK, RC, KNS, VS and MC. VS performed the NMR analysis. SV, CK, KNS, VS and RG wrote the manuscript; All authors read and corrected the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10456_2018_9616_MOESM1_ESM.doc (26 kb)
Supplementary material 1 (DOC 25 KB)
10456_2018_9616_MOESM2_ESM.ppt (692 kb)
Supplementary material 2 (PPT 691 KB)

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© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biological Sciences, Faculty of ScienceNational University of SingaporeSingaporeSingapore

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