Lung-targeted VEGF inactivation leads to an emphysema phenotype in mice.
To test the hypothesis that VEGF is important for the maintenance of alveolar structure and elastic properties in adult mice, lung-targeted ablation of the VEGF gene was accomplished through intratracheal delivery of an adeno-associated cre recombinase virus (AAV/Cre) to VEGFloxP mice, and the effects were followed for 8 wk. Control mice were similarly treated with AAV/Cre. Pulmonary VEGF levels were reduced by 86% at 5 wk postinfection but returned to normal levels by 8 wk. VEGF receptor VEGFR-2 levels were also reduced at 5 wk (by 51%) and returned to control values by 8 wk. However, alveolar septal wall destruction (increased mean linear intercept) and loss of lung elastic recoil (increased compliance) persisted for 8 wk. No decrease in alveolar cell proliferation was detected by Western blot or immunohistochemical analysis of proliferating cell nuclear antigen. Increased alveolar septal cell and bronchial epithelial cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling analysis at 5 wk. Total lung caspase-3 levels and enzyme activity were also increased at 5 wk. No obvious accumulation of inflammatory cells was observed at any time after tracheal instillation of AAV/Cre. Thus a transient decrease in pulmonary VEGF leads to increased alveolar and bronchial cell apoptosis, air space enlargement, and changes in lung elastic recoil (processes that are characteristic of emphysema) that persist for at least 8 wk.
Tang
Kechun
K
Division of Physiology, Univ. of California, San Diego, Dept. of Medicine 0623A, 9500 Gilman Dr., La Jolla, CA 92093-0623, USA.
Rossiter
Harry B
HB
Wagner
Peter D
PD
Breen
Ellen C
EC
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D004646:Emphysema / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease / Q000235:genetics; D008168:Lung / Q000473:pathology* / Q000503:physiopathology*; D008170:Lung Compliance; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D011650:Pulmonary Alveoli / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000172:deficiency* / Q000235:genetics*
D042461:Vascular Endothelial Growth Factor A