Figure 5.

Biochemically, the group of lymphangiogenic activator enzymes is diverse. It includes a metalloproteinase (ADAMTS3), serine proteases (prostate-specific antigen (PSA)/KLK3, thrombin, and plasmin), and an aspartic protease (cathepsin D). VEGF-C and VEGF-D share all activating enzymes except for the most important one: ADAMTS3. ADAMTS3 is exclusive for VEGF-C and required for the physiologic activation of VEGF-C during developmental lymphangiogenesis [41,42,43]. VEGF-C and VEGF-D are differently affected by proteolytic processing. With progressing processing, VEGF-C largely maintains its lymphangiogenic properties but loses its angiogenic properties quickly. VEGF-D behaves precisely the opposite way: processing with Cathepsin D almost completely abolishes its lymphangiogenic properties and fully unmasks its angiogenic properties [45]. Extensive exposure of both VEGF-C and VEGF-D to plasmin abolishes all VEGFR-2 and VEGFR-3 binding properties.