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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Cigarette-smoke-induced oxidative/nitrosative stress impairs VEGF- and fluid-shear-stress-mediated signaling in endothelial cells.

Authors: Edirisinghe, Indika; Arunachalam, Gnanapragasam; Wong, Chelsea; Yao, Hongwei; Rahman, Arshad; Phipps, Richard P; Jin, Zheng-Gen; Rahman, Irfan

Published In Antioxid Redox Signal, (2010 Jun 15)

Abstract: VEGF receptor 2 (VEGFR2), a tyrosine kinase receptor, is activated by VEGF and fluid shear stress (FSS), and its downstream signaling is important in the regulation of endothelial functions, such as cell migration, endothelium-dependent relaxation, and angiogenesis. Cigarette smoke (CS) is known to cause oxidative/nitrosative stress, leading to modifications of tyrosine kinase receptors and impaired downstream signaling. We hypothesized that CS-induced oxidative/nitrosative stress impairs VEGF- and FSS-mediated VEGFR2 activation, leading to endothelial dysfunction. Human lung microvascular endothelial cells and human umbilical vein endothelial cells were treated with different concentrations of cigarette smoke extract (CSE) to investigate the VEGF- or FSS-mediated VEGFR2 phosphorylation and its downstream signaling involved in endothelial function. CSE treatment impaired both VEGF- and FSS-mediated VEGFR2 phosphorylation, resulting in impaired endothelial nitric oxide synthase (eNOS) phosphorylation by Akt. CS-derived reactive oxygen/nitrogen species react with VEGFR2, rendering VEGFR2 inactive for its downstream signaling. Pretreatment with nitric oxide scavenger (PTIO), reactive oxygen species scavengers (combination of SOD with catalase), and N-acetyl-L-cysteine, significantly attenuated the CSE-induced impairment of VEGF-mediated Akt and eNOS phosphorylation. These findings suggest that CSE-induced oxidative/nitrosative stress impairs VEGF- and FSS-mediated endothelial cell function and has important implications in the pathogenesis of CS-induced pulmonary and cardiovascular diseases associated with endothelial dysfunction.

PubMed ID: 19929443 Exiting the NIEHS site

MeSH Terms: Acetylcysteine/pharmacology; Catalase/pharmacology; Cells, Cultured/drug effects; Cells, Cultured/metabolism; Cyclic N-Oxides/pharmacology; Endothelial Cells/drug effects*; Endothelial Cells/metabolism; Free Radical Scavengers/pharmacology*; Humans; Imidazoles/pharmacology; Lung/blood supply; Oxidation-Reduction; Phosphorylation/drug effects; Protein Processing, Post-Translational/drug effects*; Proto-Oncogene Proteins c-akt/physiology; Reactive Nitrogen Species/metabolism*; Reactive Oxygen Species/metabolism*; Rheology*; Signal Transduction/drug effects*; Signal Transduction/physiology; Smoke/adverse effects*; Stress, Mechanical*; Superoxide Dismutase/pharmacology; Tobacco*; Umbilical Veins; Vascular Endothelial Growth Factor A/physiology*; Vascular Endothelial Growth Factor Receptor-2/drug effects; Vascular Endothelial Growth Factor Receptor-2/physiology*

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