Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A
Miho Nozaki, … , Balamurali K. Ambati, Jayakrishna Ambati
Miho Nozaki, … , Balamurali K. Ambati, Jayakrishna Ambati
Published February 1, 2006
Citation Information: J Clin Invest. 2006;116(2):422-429. https://doi.org/10.1172/JCI26316.
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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 3

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Preexisting CNV inhibited subsequent CNV via VEGF-A. (A and B) Represent...
Preexisting CNV inhibited subsequent CNV via VEGF-A. (A and B) Representative choroidal flat mounts show that CNV lesions (insets show magnified images) were smaller in eyes (A) where preexisting laser injury (area denoted by arrow) was performed 2 days earlier compared with those in eyes (B) without prior injury. Arrowheads denote optic nerve. Scale bars: 200 μm. (C) Preexisting laser injury created 2 days before subsequent injury markedly decreased CNV in the subsequent laser spots near (∼0.75 mm) the preexisting injury and slightly decreased CNV in spots far (∼1.25 mm) from it. Preexisting laser injury created 14 days before subsequent injury in wild-type mice did not affect CNV of subsequent laser spots either near or far from preexisting injury. *P < 0.01 compared with eyes without preexisting injury; #P < 0.05 compared with far lesions in the day 2 group. n = 12 per data point. (D) Neutralizing anti–VEGF-A antibody reversed this inhibition in a dose-dependent manner. #P < 0.05 compared with no injection. n = 12 per data point. (C and D).