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Angiogenesis

, 8:349 | Cite as

Inhibition of angiogenesis by vitamin D-binding protein: Characterization of anti-endothelial activity of DBP-maf

  • Satyan Kalkunte
  • Laurent BrardEmail author
  • Cornelius O. Granai
  • Narasimha Swamy
Article

Abstract

Angiogenesis is a complex process involving coordinated steps of endothelial cell activation, proliferation, migration, tube formation and capillary sprouting with participation of intracellular signaling pathways. Regulation of angiogenesis carries tremendous potential for cancer therapy. Our earlier studies showed that vitamin D-binding protein-macrophage activating factor (DBP-maf) acts as a potent anti-angiogenic factor and inhibits tumor growth in vivo. The goal of this investigation was to understand the effect of DBP-maf on human endothelial cell (HEC) and the mechanism of angiogenesis inhibition. DBP-maf inhibited human endothelial cell (HEC) proliferation by inhibiting DNA synthesis ( \(\hbox{IC}_{50}=7.8\pm0.15\) μg/ml). DBP-maf significantly induced S- and G0/G1-phase arrest in HEC in 72 h. DBP-maf potently blocked VEGF-induced migration, tube-formation of HEC in a dose dependent manner. In addition, DBP-maf inhibited growth factor-induced microvessel sprouting in rat aortic ring assay. Moreover, DBP-maf inhibited VEGF signaling by decreasing VEGF-mediated phosphorylation of VEGFR-2 and ERK1/2, a downstream target of VEGF signaling cascade. However, Akt activation was not affected. These studies collectively demonstrate that DBP-maf inhibits angiogenesis by blocking critical steps such as HEC proliferation, migration, tube formation and microvessel sprouting. DBP-maf exerts its effect by inhibiting VEGR-2 and ERK1/2 signaling cascades. Understanding the cellular and molecular mechanisms of anti-endothelial activity of DBP-maf will allow us to develop it as an angiogenesis targeting novel drug for tumor therapy.

Keywords

angiogenesis DBP-maf endothelial cells ERK1/2 VEGF 

Notes

Acknowledgements

This work was supported by funds from the American Heart Association Scientist Development Grant 0230397N (to Dr. Swamy). We thank NIH COBRE Grant 1-P20RR018728 for providing instrumentation support. We also wish to thank Dr. Sunil Shaw for useful suggestions and discussions.

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Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Satyan Kalkunte
    • 1
  • Laurent Brard
    • 1
  • Cornelius O. Granai
    • 1
  • Narasimha Swamy
    • 1
  1. 1.Department of Pediatrics and Program in Women’s OncologyWomen and Infants’ Hospital, Brown UniversityProvidenceUSA

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