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Originally published as MBC in Press, 10.1091/mbc.E04-11-1029 on May 18, 2005

Vol. 16, Issue 8, 3488-3500, August 2005

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Cathepsin B Regulates the Intrinsic Angiogenic Threshold of Endothelial Cells{boxd}

Eunok Im, Annapurna Venkatakrishnan, and Andrius Kazlauskas

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

Submitted November 26, 2004; Revised April 8, 2005; Accepted May 11, 2005
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 protein 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 pro- and antiangiogenic agents. These observations complement and expand our appreciation of how endothelial cell–derived proteases regulate angiogenesis.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E04–11–1029) on May 18, 2005.

Abbreviations used: BBE, bovine brain extract; BRECs, bovine retinal endothelial cells; CBI, cathepsin B inhibitor; EV, the empty vector expressing cells: HS, horse serum; HUVECs, human umbilical vein endothelial cells; R2, VEGFR2.

{boxd} The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

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




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