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Open Access Highly Accessed Research article

The response of VEGF-stimulated endothelial cells to angiostatic molecules is substrate-dependent

Christina L Addison1*, Jacques E Nör2, Huijun Zhao1, Stephanie A Linn3, Peter J Polverini3 and Christie E Delaney1

Author Affiliations

1 Centre for Cancer Therapeutics, Ottawa Health Research Institute, 501 Smyth Rd., Ottawa Ontario, K1H 8L6, Canada

2 Department of Cariology, Restorative Sciences and Endodontics, School of Dentistry, University of Michigan, 1011 North University Ave., Ann Arbor Michigan 48109-1078, USA

3 Oral Medicine, Pathology and Oncology, School of Dentistry, University of Michigan, 1011 North University Ave., Ann Arbor Michigan 48109-1078, USA

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BMC Cell Biology 2005, 6:38  doi:10.1186/1471-2121-6-38

Published: 31 October 2005

Abstract

Background

The microenvironment surrounding cells can exert multiple effects on their biological responses. In particular the extracellular matrix surrounding cells can profoundly influence their behavior. It has been shown that the extracellular matrix composition in tumors is vastly different than that found in normal tissue with increased amounts of certain matrices such as collagen I. It has been previously demonstrated that VEGF stimulation of endothelial cells growing on type I collagen results in the induction of bcl-2 expression and enhanced endothelial cell survival. We sought to investigate whether this increased endothelial cell survival resulted in the failure of angiostatic molecules to inhibit angiogenesis.

Results

We now demonstrate that VEGF-induced survival on collagen I impairs the ability of three known angiostatic molecules, TSP-1, IP-10 and endostatin to inhibit endothelial cell proliferation. Apoptosis of endothelial cells, growing on collagen I, induced by TSP-1 and IP-10 was also inhibited following VEGF stimulation. In contrast, endostatin induced apoptosis in these same cells. Further analysis determined that endostatin did not decrease the expression of bcl-2 nor did it increase activation of caspase-3 in the presence of VEGF. Alternatively, it appeared that in the presence of VEGF, endostatin induced the activation of caspase-8 in endothelial cells grown on collagen I. Furthermore, only endostatin had the ability to inhibit VEGF-induced sprout formation in collagen I gels.

Conclusion

These data suggest that TSP-1, IP-10 and endostatin inhibit endothelial cells via different mechanisms and that only endostatin is effective in inhibiting angiogenic activities in the presence of collagen I. Our results suggest that the efficacy of angiostatic treatments may be impaired depending on the context of the extracellular matrix within the tumor environment and thus could impede the efficacy of angiostatic therapies.