In addition to modulating isoform bioavailability, heparin can alter bioactivity through the VEGF receptors. Low concentrations of heparin can enhance binding of VEGF165 to VEGFR2, while high concentrations of heparin can inhibit this interaction. Binding of VEGF 121 to VEGFR2 is unaffected by heparin. Heparin can inhibit interactions of VEGF121 and VEGF165 with VEGFR1, suggesting that HSPGs are necessary for VEGFR1 activity. In addition to heparin, exon seven of VEGF binds a class of receptors, known as neuropilins (Figure 1; neuropilin-1: NP-1; neu-ropilin-2: NP-2). NP-1 binds VEGF165 but not VEGF121, and is thought to serve as a VEGF coreceptor to potentiate signaling through VEGFR2. As such, NP-1 has a lower affinity for VEGF than VEGFR2. In support of the corecep-tor concept, a peptide corresponding to exon seven can inhibit VEGF165 activity by approximately 60 percent (to a level similar to VEGF121) likely by blocking VEGF-NP-1 interactions . NP-2 binds VEGF165 and VEGF145 and can mediate VEGF145 signaling.
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