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-1alpha. 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.