Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A
Journal of Clinical Investigation
VEGF-A promotes angiogenesis in many tissues. Here we report that choroidal neovascularization (CNV) incited by injury was increased by excess VEGF-A before injury but was suppressed by VEGF-A after injury. This unorthodox antiangiogenic effect was mediated via VEGFR-1 activation and VEGFR-2 deactivation, the latter via Src homology domain 2-containing (SH2-containing) tyrosine phosphatase-1 (SHP-1). The VEGFR-1-specific ligand placental growth factor-1 (PlGF-1), but not VEGF-E, which
... -E, which selectively binds VEGFR-2, mimicked these responses. Excess VEGF-A increased CNV before injury because VEGFR-1 activation was silenced by secreted protein, acidic and rich in cysteine (SPARC). The transient decline of SPARC after injury revealed a temporal window in which VEGF-A signaling was routed principally through VEGFR-1. These observations indicate that therapeutic design of VEGF-A inhibition should include consideration of the level and activity of SPARC. Nonstandard abbreviations used: ALK1, activin receptor-like kinase 1; AMD, age-related macular degeneration; BMOV, bis(maltolato)oxovanadium(IV); CNV, choroidal neovascularization; PAI-1, plasminogen activator inhibitor type I; PlGF-1, placental growth factor-1; PTP, protein tyrosine phosphatase; RPE, retinal pigmented epithelium; SH2, Src homology domain 2; SHP-1, SH2-containing tyrosine phosphatase-1; SPARC, secreted protein, acidic and rich in cysteine.