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* Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Athens, Georgia, USA;
Department of Pharmacology and Toxicology,
Vascular Biology Center,
Department of Oral Biology and Maxillofacial Pathology,
|| Department of Ophthalmology, Medical College of Georgia, August, Georgia, USA;
¶ Department of Ophthalmology, University of South Carolina, Columbia, South Carolina, USA; and
# VA Medical Center, Augusta, Georgia, USA
1Correspondence: Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, CJ-1033, 1120 15th Street, Augusta, GA 30912, USA. E-mail: aelremessy{at}mcg.edu
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.
Key Words: angiogenesis • Src • redox signaling
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