Peroxynitrite mediates VEGF's angiogenic signal and function via a nitration-independent mechanism in endothelial cells

A. B. El-Remessy, Mohamed Al-Shabrawey, D. H. Platt, Manuela Bartoli, M. A. Behzadian, N. Ghaly, N. Tsai, K. Motamed, Ruth B Caldwell

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

The modulation of angiogenic signaling by reactive oxygen species (ROS) is an emerging area of interest in cellular and vascular biology research. We provide evidence here that peroxynitrite, the powerful oxidizing and nitrating free radical, is critically involved in transduction of the VEGF signal. We tested the hypothesis that VEGF induces peroxynitrite formation, which causes tyrosine phosphorylation and mediates endothelial cell migration and tube formation, by studies of vascular endothelial cells in vitro and in a model of hypoxia-induced neovascularization in vivo. The specific peroxynitrite decomposition catalyst FeTPPs blocked VEGF-induced phosphorylation of VEGFR2 and c-Src and inhibited endothelial cell migration and tube formation. Furthermore, exogenous peroxynitrite mimicked VEGF activity in causing phosphorylation of VEGFR2 and stimulating endothelial cell growth and tube formation in vitro and new blood vessel growth in vivo. The selective nitration inhibitor epicatechin enhanced VEGF's angiogenic function in activating VEGFR2, c-Src, and promoting endothelial cell growth, migration, and tube formation in vitro and retinal neovascularization in vivo. Decomposing peroxynitrite with FeTPPs or blocking oxidation using the thiol donor NAC blocked VEGF's angiogenic functions in vitro and in vivo. In conclusion, peroxynitrite is critically involved in transducing VEGF's angiogenic signal via nitration-independent and oxidation-mediated tyrosine phosphorylation.-El-Remessy, A. B., Al-Shabrawey, M., Platt, D. H., Bartoli, M., Behzadian, M. A., Ghaly, N., Tsai, N., Motamed, K., Caldwell, R. B. Peroxynitrite mediates VEGF's angiogenic signal and function via a nitration-independent mechanism in endothelial cells.

Original languageEnglish (US)
Pages (from-to)2528-2539
Number of pages12
JournalFASEB Journal
Volume21
Issue number10
DOIs
StatePublished - Jan 1 2007

Fingerprint

Nitration
Peroxynitrous Acid
Endothelial cells
Endothelial Cells
Phosphorylation
Vascular Endothelial Growth Factor A
Cell Movement
Cell growth
Blood Vessels
Tyrosine
Growth
Retinal Neovascularization
Oxidation
Catechin
Blood vessels
Sulfhydryl Compounds
Free Radicals
Cell Biology
Reactive Oxygen Species
Signal Transduction

Keywords

  • Angiogenesis
  • Redox signaling
  • Src

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Peroxynitrite mediates VEGF's angiogenic signal and function via a nitration-independent mechanism in endothelial cells. / El-Remessy, A. B.; Al-Shabrawey, Mohamed; Platt, D. H.; Bartoli, Manuela; Behzadian, M. A.; Ghaly, N.; Tsai, N.; Motamed, K.; Caldwell, Ruth B.

In: FASEB Journal, Vol. 21, No. 10, 01.01.2007, p. 2528-2539.

Research output: Contribution to journalArticle

El-Remessy, A. B. ; Al-Shabrawey, Mohamed ; Platt, D. H. ; Bartoli, Manuela ; Behzadian, M. A. ; Ghaly, N. ; Tsai, N. ; Motamed, K. ; Caldwell, Ruth B. / Peroxynitrite mediates VEGF's angiogenic signal and function via a nitration-independent mechanism in endothelial cells. In: FASEB Journal. 2007 ; Vol. 21, No. 10. pp. 2528-2539.
@article{93a08517814e491e80a5948379335e54,
title = "Peroxynitrite mediates VEGF's angiogenic signal and function via a nitration-independent mechanism in endothelial cells",
abstract = "The modulation of angiogenic signaling by reactive oxygen species (ROS) is an emerging area of interest in cellular and vascular biology research. We provide evidence here that peroxynitrite, the powerful oxidizing and nitrating free radical, is critically involved in transduction of the VEGF signal. We tested the hypothesis that VEGF induces peroxynitrite formation, which causes tyrosine phosphorylation and mediates endothelial cell migration and tube formation, by studies of vascular endothelial cells in vitro and in a model of hypoxia-induced neovascularization in vivo. The specific peroxynitrite decomposition catalyst FeTPPs blocked VEGF-induced phosphorylation of VEGFR2 and c-Src and inhibited endothelial cell migration and tube formation. Furthermore, exogenous peroxynitrite mimicked VEGF activity in causing phosphorylation of VEGFR2 and stimulating endothelial cell growth and tube formation in vitro and new blood vessel growth in vivo. The selective nitration inhibitor epicatechin enhanced VEGF's angiogenic function in activating VEGFR2, c-Src, and promoting endothelial cell growth, migration, and tube formation in vitro and retinal neovascularization in vivo. Decomposing peroxynitrite with FeTPPs or blocking oxidation using the thiol donor NAC blocked VEGF's angiogenic functions in vitro and in vivo. In conclusion, peroxynitrite is critically involved in transducing VEGF's angiogenic signal via nitration-independent and oxidation-mediated tyrosine phosphorylation.-El-Remessy, A. B., Al-Shabrawey, M., Platt, D. H., Bartoli, M., Behzadian, M. A., Ghaly, N., Tsai, N., Motamed, K., Caldwell, R. B. Peroxynitrite mediates VEGF's angiogenic signal and function via a nitration-independent mechanism in endothelial cells.",
keywords = "Angiogenesis, Redox signaling, Src",
author = "El-Remessy, {A. B.} and Mohamed Al-Shabrawey and Platt, {D. H.} and Manuela Bartoli and Behzadian, {M. A.} and N. Ghaly and N. Tsai and K. Motamed and Caldwell, {Ruth B}",
year = "2007",
month = "1",
day = "1",
doi = "10.1096/fj.06-7854com",
language = "English (US)",
volume = "21",
pages = "2528--2539",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "10",

}

TY - JOUR

T1 - Peroxynitrite mediates VEGF's angiogenic signal and function via a nitration-independent mechanism in endothelial cells

AU - El-Remessy, A. B.

AU - Al-Shabrawey, Mohamed

AU - Platt, D. H.

AU - Bartoli, Manuela

AU - Behzadian, M. A.

AU - Ghaly, N.

AU - Tsai, N.

AU - Motamed, K.

AU - Caldwell, Ruth B

PY - 2007/1/1

Y1 - 2007/1/1

N2 - The modulation of angiogenic signaling by reactive oxygen species (ROS) is an emerging area of interest in cellular and vascular biology research. We provide evidence here that peroxynitrite, the powerful oxidizing and nitrating free radical, is critically involved in transduction of the VEGF signal. We tested the hypothesis that VEGF induces peroxynitrite formation, which causes tyrosine phosphorylation and mediates endothelial cell migration and tube formation, by studies of vascular endothelial cells in vitro and in a model of hypoxia-induced neovascularization in vivo. The specific peroxynitrite decomposition catalyst FeTPPs blocked VEGF-induced phosphorylation of VEGFR2 and c-Src and inhibited endothelial cell migration and tube formation. Furthermore, exogenous peroxynitrite mimicked VEGF activity in causing phosphorylation of VEGFR2 and stimulating endothelial cell growth and tube formation in vitro and new blood vessel growth in vivo. The selective nitration inhibitor epicatechin enhanced VEGF's angiogenic function in activating VEGFR2, c-Src, and promoting endothelial cell growth, migration, and tube formation in vitro and retinal neovascularization in vivo. Decomposing peroxynitrite with FeTPPs or blocking oxidation using the thiol donor NAC blocked VEGF's angiogenic functions in vitro and in vivo. In conclusion, peroxynitrite is critically involved in transducing VEGF's angiogenic signal via nitration-independent and oxidation-mediated tyrosine phosphorylation.-El-Remessy, A. B., Al-Shabrawey, M., Platt, D. H., Bartoli, M., Behzadian, M. A., Ghaly, N., Tsai, N., Motamed, K., Caldwell, R. B. Peroxynitrite mediates VEGF's angiogenic signal and function via a nitration-independent mechanism in endothelial cells.

AB - The modulation of angiogenic signaling by reactive oxygen species (ROS) is an emerging area of interest in cellular and vascular biology research. We provide evidence here that peroxynitrite, the powerful oxidizing and nitrating free radical, is critically involved in transduction of the VEGF signal. We tested the hypothesis that VEGF induces peroxynitrite formation, which causes tyrosine phosphorylation and mediates endothelial cell migration and tube formation, by studies of vascular endothelial cells in vitro and in a model of hypoxia-induced neovascularization in vivo. The specific peroxynitrite decomposition catalyst FeTPPs blocked VEGF-induced phosphorylation of VEGFR2 and c-Src and inhibited endothelial cell migration and tube formation. Furthermore, exogenous peroxynitrite mimicked VEGF activity in causing phosphorylation of VEGFR2 and stimulating endothelial cell growth and tube formation in vitro and new blood vessel growth in vivo. The selective nitration inhibitor epicatechin enhanced VEGF's angiogenic function in activating VEGFR2, c-Src, and promoting endothelial cell growth, migration, and tube formation in vitro and retinal neovascularization in vivo. Decomposing peroxynitrite with FeTPPs or blocking oxidation using the thiol donor NAC blocked VEGF's angiogenic functions in vitro and in vivo. In conclusion, peroxynitrite is critically involved in transducing VEGF's angiogenic signal via nitration-independent and oxidation-mediated tyrosine phosphorylation.-El-Remessy, A. B., Al-Shabrawey, M., Platt, D. H., Bartoli, M., Behzadian, M. A., Ghaly, N., Tsai, N., Motamed, K., Caldwell, R. B. Peroxynitrite mediates VEGF's angiogenic signal and function via a nitration-independent mechanism in endothelial cells.

KW - Angiogenesis

KW - Redox signaling

KW - Src

UR - http://www.scopus.com/inward/record.url?scp=34547788817&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547788817&partnerID=8YFLogxK

U2 - 10.1096/fj.06-7854com

DO - 10.1096/fj.06-7854com

M3 - Article

C2 - 17384142

AN - SCOPUS:34547788817

VL - 21

SP - 2528

EP - 2539

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 10

ER -