Abstract
BackgroundVascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2)-mediated survival signaling is critical to endothelial cell survival, maintenance of the vasculature and alveolar structure and regeneration of lung tissue. Reduced VEGF and VEGFR2 expression in emphysematous lungs has been linked to increased endothelial cell death and vascular regression. Previously, we have shown that CS down-regulated the VEGFR2 and its downstream signaling in mouse lungs. However, the VEGFR2-mediated survival signaling in response to oxidants/cigarette smoke (CS) is not known. We hypothesized that CS exposure leads to disruption of VEGFR2-mediated endothelial survival signaling in rat lungs.MethodsAdult male Sprague-Dawley rats were exposed CS for 3 days, 8 weeks and 6 months to investigate the effect of CS on VEGFR2-mediated survival signaling by measuring the Akt/PI3-kinase/eNOS downstream signaling in rat lungs.Results and DiscussionWe show that CS disrupts VEGFR2/PI3-kinase association leading to decreased Akt and eNOS phosphorylation. This may further alter the phosphorylation of the pro-apoptotic protein Bad and increase the Bad/Bcl-xl association. However, this was not associated with a significant lung cell death as evidenced by active caspase-3 levels. These data suggest that although CS altered the VEGFR2-mediated survival signaling in the rat lungs, but it was not sufficient to cause lung cell death.ConclusionThe rat lungs exposed to CS in acute, sub-chronic and chronic levels may be representative of smokers where survival signaling is altered but was not associated with lung cell death whereas emphysema is known to be associated with lung cell apoptosis.
Highlights
Maintenance of the microvasculature in the lung is critical for gas exchange, the integrity of the alveolar structure and tissue repair [1]
These data suggest that Cigarette smoke (CS) altered the VEGF receptor 2 (VEGFR2)-mediated survival signaling in the rat lungs, but it was not sufficient to cause lung cell death
The rat lungs exposed to CS in acute, sub-chronic and chronic levels may be representative of smokers where survival signaling is altered but was not associated with lung cell death whereas emphysema is known to be associated with lung cell apoptosis
Summary
Maintenance of the microvasculature in the lung is critical for gas exchange, the integrity of the alveolar structure and tissue repair [1]. Cigarette smoke (CS)-induced emphysema is characterized by enlargement of the airspaces and a loss of alveolar structure [2,3]. Endothelial cell death and the regression of lung parenchyma, capillary density seen in emphysema may be linked to this loss of the alveolar structure [4,5]. Vascular endothelial growth factor (VEGF) plays vital role in development and maintenance of vasculature and tissue regeneration [6]. Targeted disruption of VEGF gene in mice impairs blood vessel formation, growth retardation and premature death [8]. Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2)-mediated survival signaling is critical to endothelial cell survival, maintenance of the vasculature and alveolar structure and regeneration of lung tissue. Reduced VEGF and VEGFR2 expression in emphysematous lungs has been linked to increased endothelial cell death and vascular regression. We hypothesized that CS exposure leads to disruption of VEGFR2mediated endothelial survival signaling in rat lungs
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