Silky, Sticky Chimeras-Designer VEGFs Display Their Wares

Abstract

See related articles, pages 1460–1467 and 1468–1475 To the casual observer of the VEGF field, the panoply of players involved already looks sufficiently intimidating; 5 VEGF genes (A,B,C,D and E) with multiple splicing variants encoding proteins of varied functionality, 3 high-affinity tyrosine kinase receptors (VEGF-R1, 2 and 3), and at least 2 nontyrosine kinase receptors (neuropilin-1 and 2). One would imagine that with such a variety we would have encountered by now all possible variations on the theme of VEGF control of new vessel growth, arterial or lymphatic. But one would be wrong. Two reports in this issue of Circulation Research by Kari Alitalo and colleagues demonstrate how various VEGF domains dictate hitherto unappreciated biological nuances of vascular growth and how these can be combined into “designer” VEGFs with new activities not present in parent molecules.1,2 Principal VEGF-A domains include a signal peptide sequence, a VEGF homology domain (VHD) common to all VEGF but dictating specific VEGF receptor binding properties (VEGF-R1 and VEGF- R 2 in the case of VEGF-A VHD), and a heparin binding domain (HBD) encoded by exons 6 and 7 in VEGF189 or a shorter HBD encoded only by exon 7 in VEGF-A165. Exon 7 also encodes a neurolin-1 binding domain present in both VEGF-A165 and A189 (Figure). Similarly, VEGF-C principal domains include the signal peptide domain and VEGF-C VHD (in this case dictating VEGF- R 2 and VEGF-R3 binding) flanked by N- and C-terminal domains that normally undergo proteolytic process to form the mature protein (Figure). The C-terminal domain of VEGF-C, because of its cysteine-rich sequences eliciting comparisons with a protein component of silk, has been termed a silk homology domain. VEGF and VEGF chimera domain structure. Domain structure of VEGF-A189, VEGF-A165 and VEGF-C (top) and …