Comparison of Expression of Cathepsins B and L and MMP2 in Endothelial Cells and in Capillary Sprouting in Collagen Gel

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Abstract
The lysosomal cysteine proteinases cathepsins B and L are known to play an important role in the invasive growth of tumor cells, but their association with angiogenesis has been less well studied. The aim of this study was to determine the possible role of endothelial cell-associated cathepsins B and L in induced capillary growth in the aorta ring model of angiogenesis. Specific inhibitors of cysteine proteinases did not inhibit capillary growth in aorta ring culture and only slightly inhibited the degradation of surrounding collagen. In contrast, strong inhibition of both processes by the matrix metalloproteinase inhibitor BB-94 was observed, indicating the importance of endogenous MMP production in angiogenesis. In support of this finding, we demonstrated a significant increase in endogenous endothelial mRNA of MMP2, but not of cathepsins B and L, in proliferating primary human dermal microvascular endothelial cells (HMVEC-d) in culture. However, MMP2 mRNA expression was increased only when the cells were embedded in collagen but not when they were grown on plastic, regardless of the addition of the growth factors VEGF or bFGF. Moreover, on plastic the impairment of MMP2 induction by growth factors was observed. The differential effect of growth factors implies the crosstalk with integrin signaling as a consequence of binding to the different matrix. This study suggests that endothelial cell-associated cathepsins B and L are not involved in the invasive growth of capillaries from existing blood vessels and that the presence of collagen is necessary for MMP2 expression in endothelial cells.