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

Research output: Contribution to journalArticle

70 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)422-429
Number of pages8
JournalJournal of Clinical Investigation
Volume116
Issue number2
DOIs
StatePublished - Feb 1 2006

ASJC Scopus subject areas

  • Medicine(all)

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    Nozaki, M., Sakurai, E., Raisler, B. J., Baffi, J. Z., Witta, J., Ogura, Y., Brekken, R. A., Sage, E. H., Ambati, B. K., & Ambati, J. (2006). Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A. Journal of Clinical Investigation, 116(2), 422-429. https://doi.org/10.1172/JCI26316