Novel role of p66shc in ROS-dependent VEGF signaling and angiogenesis in endothelial cells

Jin Oshikawa, Seok Jo Kim, Eiji Furuta, Cristiana Caliceti, Gin Fu Chen, Ronald D. McKinney, Frank Kuhr, Irena Levitan, Tohru Fukai, Masuko Ushio-Fukai

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

A longevity adaptor protein, is demonstrated as a key regulator of reactive oxygen species (ROS) metabolism involved in aging and cardiovascular diseases. Vascular endothelial growth factor (VEGF) stimulates endothe-lial cell (EC) migration and proliferation primarily through the VEGF receptor-2 (VEGFR2). We have shown that ROS derived from Rac1-dependent NADPH oxidase are involved in VEGFR2 autophosphor-ylation and angiogenic-related responses in ECs. However, a role of p66Shc in VEGF signaling and physiological responses in ECs is unknown. Here we show that VEGF promotes p66Shc phosphoryla-tion at Ser36 through the JNK/ERK or PKC pathway as well as Rac1 binding to a nonphosphorylated form of p66Shc in ECs. Depletion of endogenous p66Shc with short interfering RNA inhibits VEGF-induced Rac1 activity and ROS production. Fractionation of caveolin-enriched lipid raft demonstrates that p66Shc plays a critical role in VEGFR2 phosphorylation in caveolae/lipid rafts as well as downstream p38MAP kinase activation. This in turn stimulates VEGF-induced EC migration, proliferation, and capillary-like tube formation. These studies uncover a novel role of p66Shc as a positive regulator for ROS-dependent VEGFR2 signaling linked to angiogen-esis in ECs and suggest p66Shc as a potential therapeutic target for various angiogenesis-dependent diseases.

Original languageEnglish (US)
Pages (from-to)H724-H732
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume302
Issue number3
DOIs
StatePublished - Feb 2012

Keywords

  • Reactive oxygen species
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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