Figure 2.

Most diversity among the hemangiogenic VEGFs is achieved by alternative splicing. Nevertheless, proteolytic processing of VEGF-A (A) [19] and placenta growth factor (PlGF) [32] (C) can convert the longer, heparin-binding isoforms into more soluble shorter species. (B) VEGF-B is a special case. Alternative splicing results in two isoforms that translate the same nucleotide sequence in two different frames resulting in a heparin-binding and a soluble isoform [33,34]. Due to the near-perfect cleavage context [35], thrombin has been suspected to be the responsible protease for VEGF-B₁₈₆ cleavage [36]. Prothrombin is indeed expressed by 293T cells [37], in which the cleavage has been demonstrated [33]. Plasmin cleaves VEGF-B₁₈₆ at at least four different sites, of which the two most likely predicted sites are indicated. Importantly, the predicted plasmin cleavage between Arg137 and Ala138 removes the interaction epitope for neuropilin-1 binding [33] Semi-transparent, blurry arrows indicate cleavages, for which only the approximate position is known. The figure shows only the most sensitive site from the plasmin cleavages of VEGF-A since prolonged incubation results in progressing degradation [30]. VEGF-B₁₈₆ appears to be progressively degraded by plasmin as well [33]. For VEGF-A and PlGF, the numbering is according to the longest shown isoform. VEGF-A is cleaved not only by MMP3 but also in a similar fashion by MMP7, MMP9, MMP19, and - less efficiently - by MMP1 and MMP16 [30].