Localized cysteine sulfenic acid formation by vascular endothelial growth factor

Role in endothelial cell migration and angiogenesis

Nihal Kaplan, Norifumi Urao, Eiji Furuta, Seok Jo Kim, Masooma Razvi, Yoshimasa Nakamura, Ronald D. McKinney, Leslie B. Poole, Tohru Fukai, Masuko Fukai

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Reactive oxygen species (ROS) are important mediators for VEGF receptor 2 (VEGFR2) signalling involved in angiogenesis. The initial product of Cys oxidation, cysteine sulfenic acid (Cys-OH), is a key intermediate in redox signal transduction; however, its role in VEGF signalling is unknown. We have previously demonstrated IQGAP1 as a VEGFR2 binding scaffold protein involved in ROS-dependent EC migration and post-ischemic angiogenesis. Using a biotin-labelled Cys-OH trapping reagent, we show that VEGF increases protein-Cys-OH formation at the lamellipodial leading edge where it co-localizes with NADPH oxidase and IQGAP1 in migrating ECs, which is prevented by IQGAP1 siRNA or trapping of Cys-OH with dimedone. VEGF increases IQGAP1-Cys-OH formation, which is prevented by N-acetyl cysteine or dimedone, which inhibits VEGF-induced EC migration and capillary network formation. In vivo, hindlimb ischemia in mice increases Cys-OH formation in small vessels and IQGAP1 in ischemic tissues. In summary, VEGF stimulates localized formation of Cys-OH-IQGAP1 at the leading edge, thereby promoting directional EC migration, which may contribute to post-natal angiogenesis in vivo. Thus, targeting Cys-oxidized proteins at specific compartments may be the potential therapeutic strategy for various angiogenesis-dependent diseases.

Original languageEnglish (US)
Pages (from-to)1124-1135
Number of pages12
JournalFree Radical Research
Volume45
Issue number10
DOIs
StatePublished - Oct 1 2011
Externally publishedYes

Fingerprint

Endothelial cells
Vascular Endothelial Growth Factor A
Cell Movement
Endothelial Cells
Vascular Endothelial Growth Factor Receptor
Reactive Oxygen Species
Acetylcysteine
Signal transduction
Proteins
NADPH Oxidase
Hindlimb
Biotin
Scaffolds
Small Interfering RNA
Oxidation-Reduction
Cysteine
Signal Transduction
Carrier Proteins
Ischemia
cysteinesulfenic acid

Keywords

  • Angiogenesis
  • Cell motility
  • Endothelial cells
  • NADPH oxidase
  • Reactive oxygen species (ROS)
  • Redox signalling
  • Sulfenic acid
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Biochemistry

Cite this

Localized cysteine sulfenic acid formation by vascular endothelial growth factor : Role in endothelial cell migration and angiogenesis. / Kaplan, Nihal; Urao, Norifumi; Furuta, Eiji; Kim, Seok Jo; Razvi, Masooma; Nakamura, Yoshimasa; McKinney, Ronald D.; Poole, Leslie B.; Fukai, Tohru; Fukai, Masuko.

In: Free Radical Research, Vol. 45, No. 10, 01.10.2011, p. 1124-1135.

Research output: Contribution to journalArticle

Kaplan, Nihal ; Urao, Norifumi ; Furuta, Eiji ; Kim, Seok Jo ; Razvi, Masooma ; Nakamura, Yoshimasa ; McKinney, Ronald D. ; Poole, Leslie B. ; Fukai, Tohru ; Fukai, Masuko. / Localized cysteine sulfenic acid formation by vascular endothelial growth factor : Role in endothelial cell migration and angiogenesis. In: Free Radical Research. 2011 ; Vol. 45, No. 10. pp. 1124-1135.
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