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MBC in Press, published online ahead of print May 18, 2005
Mol. Biol. Cell 10.1091/mbc.E04-11-1029

A more recent version of this article appeared on August 1, 2005
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Submitted on November 26, 2004
Revised on April 8, 2005
Accepted on May 11, 2005

Cathepsin B Regulates the Intrinsic Angiogenic Threshold of Endothelial Cells

Eunok Im, Annapurna Venkatakrishnan, and Andrius Kazlauskas

Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114

Monitoring Editor: Jean Schwarzbauer

The lysosomal protease cathepsin B has been implicated in a variety of pathologies including pancreatitis, tumor angiogenesis and neuronal diseases. We used a tube formation assay to investigate the role of cathepsin B in angiogenesis. When cultured between two layers of collagen I, primary endothelial cells formed tubes in response to exogenously added VEGF. Overexpressing cathepsin B reduced the VEGF-dependent tube response, whereas pharmacologically or molecularly suppressing cathepsin B eliminated the dependence on exogenous VEGF. However, tube formation still required VEGF receptor activity, which suggested that endothelial cells generated VEGF. Indeed, VEGF mRNA and proteins was detectable in cells treated with cathepsin B inhibitor, which correlated with a rise in the level of HIF-1{alpha}. In addition to boosting the level of proangiogenic factors, blocking cathepsin B activity reduced the amount of the antiangiogenic protein endostatin. Thus endothelial cells have the intrinsic capacity to generate proand antiangiogenic agents. These observations complement and expand our appreciation of how endothelial cell-derived proteases regulate angiogenesis.

Address correspondence to: Andrius Kazlauskas (ak{at}eri.harvard.edu)




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