Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD: morphological impact of VEGFR-2 inhibition

1 Novartis Institute for Biomedical Research, Horsham, and 2 Respiratory Medicine Unit, Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom; and 3 Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York Submitted 14 March 2005 ; accepted in final form 16 November 2005 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. kinase insert domain receptor; neuropilin-1; vascular endothelial growth factor receptor-2; chronic obstructive pulmonary disease Address for reprint requests and other correspondence: I. Rahman, Dept. of Environmental Medicine, Univ. of Rochester Medical Center, Box 850, 601 Elmwood Ave., Rochester, NY 14642 (e-mail: irfan_rahman{at}urmc.rochester.edu )