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1 Novartis Institute for Biomedical Research, Horsham, United Kingdom
2 Respiratory Medicine Unit, University of Edinburgh, Edinburgh, United Kingdom
* To whom correspondence should be addressed. E-mail: Irfan_Rahman{at}urmc.rochester.edu.
Vascular endothelial growth factor (VEGF) is fundamental in the development and maintenance of the vasculature. VEGF 165 (VEGF165) signaling through the VEGF receptor 2 (VEGFR2)/kinase insert domain receptor (KDR) is a highly regulated process, involving the formation of a tertiary complex with glypican-1 (GYP-1) and neuropilin-1 (NRP-1). Both VEGF and VEGFR2 expression are reduced in emphysematous lungs, however the mechanism of regulation of VEGF165 signaling through the VEGFR2 complex in response to cigarette smoke exposure in vivo, and in smokers with and without chronic obstructive pulmonary disease (COPD) is still unknown. We hypothesize that cigarette smoke exposure disrupts the VEGF165-VEGFR2 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 VEGFR2 levels in rat lungs and that VEGF, VEGFR2, GYP-1 and NRP-1 expression in both the lungs of smokers and patients with COPD are also reduced, as compared to non-smokers. Moreover, our data suggests that specific inhibition of VEGFR2 alone with NVP-AAD777 would appear not to result in emphysema in the adult rat lung. As both VEGF165 and VEGFR2 expression is reduced in emphysematous lungs, decreased GYP-1 and NRP-1 expression may yet further disrupt VEGF165-VEGFR2 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 VEGF165-VEGFR2 complex may promote endothelial cell survival and help to ameliorate emphysema.
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