VEGFR-2 inhibition augments cigarette smoke-induced oxidative stress and inflammatory responses leading to endothelial dysfunction.
Vascular endothelial growth factor (VEGF) induces phosphorylation of VEGF receptor-2 (VEGFR-2) and activates the downstream signaling pathway resulting in endothelial cell migration, proliferation, and survival. Cigarette smoking is associated with abnormal vascular and endothelial function, leading to airspace enlargement. Herein, we investigated the mechanism of cigarette smoke (CS) -induced endothelial dysfunction by studying the VEGF-VEGFR-2 signaling in mouse lung and human endothelial cells. CS exposure caused oxidative stress, as shown by increased levels of 4-hydroxy-2-nonenal-adducts in mouse lung and reactive oxygen species generation in human lung microvascular endothelial cells (HMVEC-Ls). Inhibition of VEGFR-2 by a specific kinase inhibitor (NVP-AAD777) enhanced the CS-induced oxidative stress, causing augmented inflammatory cell influx and proinflammatory mediators release in mouse lung. The levels of endothelial nitric oxide synthase (eNOS) and phosphorylated (p) -eNOS in the lungs of mice exposed to CS and/or treated with VEGFR-2 inhibitor were decreased. CS down-regulated VEGFR-2 expression, eNOS levels, and VEGF-induced VEGFR-2 phosphorylation in HMVEC-Ls, resulting in impaired VEGF-induced endothelial cell migration and angiogenesis. Overall, these data show that inhibition of VEGFR-2 augmented CS-induced oxidative stress and inflammatory responses leading to endothelial dysfunction. This explains the mechanism of endothelial dysfunction in smokers and has implications in understanding the pathogenesis of pulmonary and cardiovascular diseases.
Edirisinghe
Indika
I
Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USA.
Yang
Se-Ran
SR
Yao
Hongwei
H
Rajendrasozhan
Saravanan
S
Caito
Samuel
S
Adenuga
David
D
Wong
Chelsea
C
Rahman
Arshad
A
Phipps
Richard P
RP
Jin
Zheng-Gen
ZG
Rahman
Irfan
I
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D012907:Smoking / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III; D040301:Vascular Endothelial Growth Factor Receptor-2