Figure 3.

Alternative splicing of the vascular endothelial growth factor A (VEGFA) gene. (a) Structure of the VEGFA gene, showing translational start (denoted by arrow in exon 1) and stop codons, VEGF receptor binding sites, and heparin and neuropilin binding sites. (b) Splice variant families of the VEGF-A gene: VEGF_xxxa and VEGF_xxxb. The site of the stop codon is shown only in VEGF-A₂₀₆a and b but is in the corresponding location for the other members of each splice variant family. The angiogenic, algesic isoforms of VEGF-A_xxxa are shown on the left, and the VEGF-A_xxxb antiangiogenic, analgesic isoforms on the right. Selection of the proximal splice site in exon 8 results in the inclusion of exons 8a and 8b, and use of the proximal stop codon in exon 8a, resulting in a family of splice variants with the C terminal sequence CDKPRR. Use of the distal splice site results in the inclusion of only exon 8b, and thereby introduces a frame shift and use of the different stop codon in exon 8b. The family of splice variants that contains exon 8b has the C terminal sequence SLTRKD. Note that each family comprises several members, all of which contain binding sites for both VEGFR1 and VEGFR2, but which have variable heparin and neuropilin binding. For example, VEGF-A₁₂₁a binds neither heparin nor neuropilin, whereas VEGF-A₁₆₅a binds both heparin and neuropilin. VEGF-A₁₆₅b heparin binding is less than for VEGF-A₁₈₉a but greater than for VEGF-A₁₄₅a because of the differences in exon 6 splicing. (c) There is one report in the literature of a further splice variant of VEGF-A, VEGF-Ax, which contains exons 8a and 8b but exhibits translational read-through and, thus, uses the 8b stop codon. Therefore, VEGF-Ax has the VEGF-A_xxxb C terminal sequence and antiangiogenic activity [124].