Figure 2.

The schematic summary of cathepsins’ role in inducing angiogenesis. A: Generally, cathepsins expressed in cancer cells significantly stimulate the expression of matrix metalloprotease-9 (MMP-9) and vascular endothelial growth factor (VEGF). B: They enhance cathepsins’ ability to degrade the extracellular matrix (ECM) and promote the infiltration of vascular endothelial cells. C: Additionally, certain cathepsins specifically induce angiogenesis by creating an optimal environment for vascular endothelial cells. Cathepsin B in immune cells cleaves surface CD18, enabling leukocytes to detach from endothelial ICAM-1-mediated adhesion to vessels. The shedding of CD18 facilitates leukocyte extravasation and subsequent IL-1β-induced angiogenesis. D: In endothelial cells under hypoxia, cathepsin K activates cleaved Notch1 and its downstream signaling pathways, including phosphorylated Akt. Cathepsin K also enhances the proliferation, invasion, and tubal formation of endothelial cells as well as the presence of CD31⁺/c-Kit⁺ progenitor-like cells. E: Cathepsin S is linked with the activation of endothelial progenitor-like cells and the phosphorylation of Akt and mTOR in ischemic tissues. Uniquely, cathepsin S cleaves anti-angiogenic peptides and facilitates the production of pro-angiogenic peptide by cleaving laminin-5.