Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs

Specific proteolytic cleavages turn on, modify, or off the activity of vascular endothelial growth factors (VEGFs). Proteolysis is most prominent among lymph­angiogenic VEGF-C and VEGF-D, which are synthesized as precursors that need to undergo enzymatic removal their C- N-terminal propeptides before they can activate receptors. At least five different proteases mediate activating cleavage VEGF-C: plasmin, ADAMTS3, prostate-specific antigen, cathepsin D, thrombin. All these except for ADAMTS3 also VEGF-D. Processing by results in distinct forms “mature” factors, differ affinity receptor activation potential. The “default” VEGF-C-activating enzyme does not therefore, VEGF-D do function contexts. itself regulated contexts proteases. During embryonic development, activates VEGF-C. other likely important non-developmental lymphangiogenesis during, e.g., tissue regeneration, inflammation, immune response, pathological tumor-associated lymphangiogenesis. better we understand events at molecular level, greater our chances developing successful therapies targeting diseases involving lymphatics such lymphedema cancer.