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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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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VEGF-A decreased CNV through VEGFR-1–induced negative transduction of VE...
VEGF-A decreased CNV through VEGFR-1–induced negative transduction of VEGFR-2 via SHP-1. (A) Representative figure shows VEGFR-1 phosphorylation levels in RPE/choroid of eyes before injury (control) and 30 minutes after intravitreous injection of PBS or VEGF-A, 1 day after injury. n = 5. WB, Western blot. (B) Representative figure shows that VEGF-A, injected 1 day after laser injury, increased interaction of SHP-1 with VEGFR-2 and reduced VEGFR-2 phosphorylation at 30 minutes after injection, 1 day after injury, and before injury (control), without affecting VEGFR-2 expression. Densitometric ratios of SHP-1 to total VEGFR-2 and of phosphorylated (P) to total (T) VEGFR-1 or VEGFR-2 are shown before (control) and after injury. Ratios were normalized to control values. n = 5. (C) VEGF-A–induced CNV suppression was abrogated by BMOV (0.16 μmol) and sodium stibogluconate (SSG) (0.56 nmol) in wild-type mice. n = 12 per data point. (D) VEGF-A did not significantly suppress CNV in Shp1–/– mice (n = 12 per data point; P = 0.44). *P < 0.05 compared with PBS. VEGF-A, 0.1 pmol.