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

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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.

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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

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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.

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Authors and Affiliations

  1. Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543, Singapore

    Shruthi Venugopal, Chieh Kao, Ritu Chandna, Konerirajapuram N. Sulochana, Vivekanandan Subramanian, Mo Chen, R. Manjunatha Kini & Ruowen Ge

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  1. Shruthi Venugopal
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  2. Chieh Kao
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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.

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Correspondence to Ruowen Ge.

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The authors declare that they have no conflict of interest.

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Venugopal, S., Kao, C., Chandna, R. et al. Angio-3, a 10-residue peptide derived from human plasminogen kringle 3, suppresses tumor growth in mice via impeding both angiogenesis and vascular permeability. Angiogenesis 21, 653–665 (2018). https://doi.org/10.1007/s10456-018-9616-7

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