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Cigarette smoke mediated oxidative/nitrosative stress impairs VEGF‐ and fluid shear stress‐induced endothelial function

VEGFR2, a tyrosine kinase receptor, is induced by VEGF and fluid shear stress (FSS) in endothelial cells. VEGFR2 downstream signaling is important in the regulation of normal endothelial functions such as cell migration, endothelial dependent relaxation and angiogenesis. Cigarette smoke (CS)‐induced oxidative/nitrosative stress causes modifications of the tyrosine kinase receptors and impaired cellular signaling. We hypothesized that CS‐induced reactive nitrogen/oxygen species (RNOS) impair VEGF‐ and FSS‐induced VEGFR2 kinase signaling leading to endothelial dysfunction. Human lung microvascular endothelial cells were treated with cigarette smoke extract (CSE; 0.1–0.5%) to investigate VEGF‐ or FSS‐induced VEGFR2 phosphorylation and downstream signaling that may influence endothelial function. CSE downregulated both VEGF‐ and FSS‐induced VEGFR2 phosphorylation and its downstream signaling via Akt resulting in impaired eNOS phosphorylation. CS‐derived 4‐hydroxy‐2‐nonenal and reactive nitrogen species interacted with VEGFR2 rendering VEGFR2 inactive for downstream signaling. Pretreatment of cells with the thiol antioxidant N‐acetyl‐L‐cysteine significantly attenuated the CSE‐mediated VEGF‐ and FSS‐ induced impaired VEGFR2 phosphorylation. These new findings suggest that CS‐induced RNOS impairs VEGF‐ and FSS‐induced VEGFR2 signaling leading to endothelial dysfunction in smokers. These data may have implications in the pathogenesis of pulmonary and cardiovascular diseases.