title: Localized cysteine sulfenic acid formation by vascular endothelial growth factor: role in endothelial cell migration and angiogenesis.
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.
authors: Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors: Nihal
authors: N
authors: Kaplan
authors: Norifumi
authors: N
authors: Urao
authors: Eiji
authors: E
authors: Furuta
authors: Seok-Jo
authors: SJ
authors: Kim
authors: Masooma
authors: M
authors: Razvi
authors: Yoshimasa
authors: Y
authors: Nakamura
authors: Ronald D
authors: RD
authors: McKinney
authors: Leslie B
authors: LB
authors: Poole
authors: Tohru
authors: T
authors: Fukai
authors: Masuko
authors: M
authors: Ushio-Fukai
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D019255:NADPH Oxidases / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013434:Sulfenic Acids; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000494:pharmacology; D020703:ras GTPase-Activating Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; C101203:IQ motif containing GTPase activating protein 1; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013434:Sulfenic Acids; D042461:Vascular Endothelial Growth Factor A; D020703:ras GTPase-Activating Proteins; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; C100870:cysteinesulfenic acid; D003545:Cysteine