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Angiogenesis, the process by which new branches sprout from existing vessels, requires the degradation of the vascular basement membrane and remodeling of the ECM in order to allow endothelial cells to migrate and invade into the surrounding tissues. Serine, metallo, and cysteine proteinases are 3 types of a family of enzymes that proteolytically degrade various components of extracellular matrix. These proteases release various growth factors and also increase adhesive molecules and signaling pathway molecules upon their activation, which plays a significant role in angiogenesis. Downregulation of these molecules by antisense/siRNA or synthetic inhibitors decreases the levels of these molecules, inhibits the release of growth factors, and decreases the levels of various signaling pathway molecules, thereby leading to the inhibition of angiogenesis. Furthermore, MMPs degrade specific substrates and release angiogenic inhibitors which inhibit angiogenesis. Downregulation of 2 molecules, such as uPA and uPAR, uPAR and MMP-9, or Cathepsin B and MMP-9, are more effective to inhibit angiogenesis rather than downregulation of single molecules. However, careful testing of these combinations are most important because multiple effects of these combinations play a significant role in angiogenesis.