Cigarette smoke-mediated oxidative stress, shear stress, and endothelial dysfunction: role of VEGFR2.
Vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2), a tyrosine kinase receptor, is activated by VEGF and fluid shear stress (FSS), and its downstream signaling is important in regulation of endothelial functions, such as cell migration, endothelium-dependent relaxation, and angiogenesis. Inhibition of VEGFR2 augments cigarette smoke (CS)-induced oxidative stress and inflammatory responses leading to endothelial dysfunction. CS-derived reactive oxygen/nitrogen species interact with VEGFR2, causing posttranslational modifications that render VEGFR2 inactive for downstream signaling, resulting in endothelial dysfunction. CS-mediated oxidants/carbonyl stress decreases SIRT1 levels and causes eNOS acetylation, which has ramifications in endothelial dysfunction. CS also affects endothelial cell survival pathway by disrupting VEGF- and FSS-mediated VEGFR2/PI3-kinase signaling, leading to decreased Akt phosphorylation and eNOS acetylation. We describe here the mechanisms whereby CS alters VEGF- and FSS-mediated VEGFR2-eNOS signaling, which may have implications for understanding the pathogenesis of pulmonary and cardiovascular diseases.
Edirisinghe
Indika
I
National Center for Food Safety and Technology, Illinois Institute of Technology, Summit Argo, Illinois, USA.
Rahman
Irfan
I
D000818:Animals; D002465:Cell Movement / Q000276:immunology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D018836:Inflammation Mediators / Q000009:adverse effects / Q000502:physiology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D012907:Smoking / Q000009:adverse effects* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013314:Stress, Mechanical; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology*
D018836:Inflammation Mediators; D040301:Vascular Endothelial Growth Factor Receptor-2