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

Abstract

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

The Key Gene Expression Patterns and Prognostic Factors in Malignant Transformation from Enchondroma to Chondrosarcoma

“…The VEGF family is a key mediator of angiogenesis (7). Blocking VEGFA is used to treat tumors (20). In one study, patients benefited from Ramncirumab, a monoclonal antibody that binds to VEGFR-2.…”

Increase in Chymase-Positive Mast Cells in Recurrent Pleomorphic Adenoma and Carcinoma Ex Pleomorphic Adenoma of the Parotid Gland

“…For example, Muramatsu et al [ 30 ] have reported that the angiogenesis in an Ang I-infused sponge-implanted model was markedly suppressed by treatment with a chymase-specific inhibitor, and this suppression was achieved through the inhibitory effects on the chymase-Ang II-VEGF-dependent pathway, indicating that chymase-generated Ang II participates in the neovascularization process through the increase in VEGF expression. As is well known, both angiogenesis and lymphangiogenesis in malignant tumors is accelerated by VEGF, and they may increase the frequency of blood and lymphatic metastases [ 31 ]. On the other hand, angiogenesis could also increase nutrient supply and contribute to tumor growth.…”

Regulation of VEGFR Signalling in Lymphatic Vascular Development and Disease: An Update

“…Alternative splicing liberates a variety of VEGFA species which differ in their capacity to bind VEGFRs, co-receptors and ECM components [ 37 , 43 ]. In contrast, VEGFC and VEGFD comprise a central VEGF homology domain (VHD), flanked by N- and C-terminal pro-peptides that are proteolytically cleaved to generate mature growth factors with maximal affinity for binding to and activating VEGFR3 [ 50 ]. Proteases established to mediate VEGFC cleavage include ADAMTS3 [ 25 ], Adamts14 [ 51 ] (in zebrafish), plasmin [ 52 ], thrombin [ 53 ], kallikrein-related peptidase 3 (KLK3) [ 54 ] and cathepsin D [ 54 ].…”