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 Ushio-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

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; Ushio-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 ; Ushio-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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AU - Kim, Seok Jo

AU - Razvi, Masooma

AU - Nakamura, Yoshimasa

AU - McKinney, Ronald D.

AU - Poole, Leslie B.

AU - Fukai, Tohru

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AB - 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.

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