Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A
Miho Nozaki, Eiji Sakurai, Brian J. Raisler, Judit Z. Baffi, Jassir Witta, Yuichiro Ogura, Rolf A. Brekken, E. Helene Sage, Balamurali K. Ambati, Jayakrishna Ambati
Miho Nozaki, Eiji Sakurai, Brian J. Raisler, Judit Z. Baffi, Jassir Witta, Yuichiro Ogura, Rolf A. Brekken, E. Helene Sage, Balamurali K. Ambati, Jayakrishna Ambati
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Research Article Ophthalmology

Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A

Abstract

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.

Authors

Miho Nozaki, Eiji Sakurai, Brian J. Raisler, Judit Z. Baffi, Jassir Witta, Yuichiro Ogura, Rolf A. Brekken, E. Helene Sage, Balamurali K. Ambati, Jayakrishna Ambati

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Figure 6

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SPARC regulated VEGF-A effects on CNV. (A) Constitutive (control) RPE/ch...
SPARC regulated VEGF-A effects on CNV. (A) Constitutive (control) RPE/choroid expression of SPARC was decreased 1 day after laser injury and recovered 2 days after injury. Figure is representative of 3 experiments. (B and C) Immunoprecipitation of 3 independent samples revealed that VEGF-A interacted with SPARC (B) but not IGF binding protein-3 (IGFBP-3) (C) in vivo. (D) CNV inhibition by VEGF-A injected 1 day after injury was abolished by recombinant human SPARC (rhSPARC) and restored by neutralizing anti-SPARC Ab (80 pmol). *P < 0.05 compared with PBS. Recombinant SPARC injection alone (white bar) did not change CNV compared with PBS. (E) Neutralizing anti-SPARC Ab (26.7 pmol) but not control mouse IgG abrogated CNV increase induced by VEGF-A 1 day before injury. *P < 0.05 compared with PBS. (F) VEGF-A injected 1 day before laser injury increased CNV in SPARC+/+ mice but not in SPARC–/– mice. VEGF-A injected 1 day after laser injury decreased CNV in SPARC+/+ and SPARC–/– mice. *P < 0.05 compared with PBS injection on the same day. VEGF-A, 0.1 pmol. n = 10–14 per data point (D–F).