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 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.
Digital Object Identifier (DOI)
Nozaki, Miho; Sakurai, Eiji; Raisler, Brian J.; Baffi, Judit Z.; Witta, Jassir; Ogura, Yuichiro; Brekken, Rolf A.; Sage, E Helene; Ambati, Balamurali K.; and Ambati, Jayakrishna, "Loss of SPARC-Mediated VEGFR-1 Suppression After Injury Reveals a Novel Antiangiogenic Activity of VEGF-A" (2006). Ophthalmology and Visual Science Faculty Publications. 6.