Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD: morphological impact of VEGFR-2 inhibition.
VEGF is fundamental in the development and maintenance of the vasculature. VEGF(165) signaling through VEGF receptor (VEGFR)-2/kinase insert domain receptor (KDR) is a highly regulated process involving the formation of a tertiary complex with glypican (GYP)-1 and neuropilin (NRP)-1. Both VEGF and VEGFR-2 expression are reduced in emphysematous lungs; however, the mechanism of regulation of VEGF(165) signaling through the VEGFR-2 complex in response to cigarette smoke exposure in vivo, and in smokers with and without chronic obstructive pulmonary disease (COPD), is still unknown. We hypothesized that cigarette smoke exposure disrupts the VEGF(165)-VEGFR-2 complex, a potential mechanism in the pathogenesis of emphysema. We show that cigarette smoke exposure reduces NRP-1 and GYP-1 as well as VEGF and VEGFR-2 levels in rat lungs and that VEGF, VEGFR-2, GYP-1, and NRP-1 expression in the lungs of both smokers and patients with COPD are also reduced compared with nonsmokers. Moreover, our data suggest that specific inhibition of VEGFR-2 alone with NVP-AAD777 would appear not to result in emphysema in the adult rat lung. As both VEGF(165) and VEGFR-2 expression are reduced in emphysematous lungs, decreased GYP-1 and NRP-1 expression may yet further disrupt VEGF(165)-VEGFR-2 signaling. Whether or not this by itself is critical for inducing endothelial cell apoptosis and decreased vascularization of the lung seen in emphysema patients is still unclear at present. However, targeted therapies to restore VEGF(165)-VEGFR-2 complex may promote endothelial cell survival and help to ameliorate emphysema.
Marwick
John A
JA
Department of Environmental Medicine, University of Rochester Medical Center, Box 850, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Stevenson
Christopher S
CS
Giddings
June
J
MacNee
William
W
Butler
Keith
K
Rahman
Irfan
I
Kirkham
Paul A
PA
D000818:Animals; D005541:Forced Expiratory Volume; D006801:Humans; D008168:Lung / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects / Q000502:physiology*
D012906:Smoke; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2