Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization.
BACKGROUND
Bronchopulmonary dysplasia (BPD) and pulmonary emphysema, both significant global health problems, are characterized by a loss of alveoli. Vascular endothelial growth factor (VEGF) is a trophic factor required for endothelial cell survival and is abundantly expressed in the lung.


RESULTS
We report that VEGF blockade decreases lung VEGF and VEGF receptor 2 (VEGFR-2) expression in newborn rats and impairs alveolar development, leading to alveolar simplification and loss of lung capillaries, mimicking BPD. In hyperoxia-induced BPD in newborn rats, air space enlargement and loss of lung capillaries are associated with decreased lung VEGF and VEGFR-2 expression. Postnatal intratracheal adenovirus-mediated VEGF gene therapy improves survival, promotes lung capillary formation, and preserves alveolar development in this model of irreversible lung injury. Combined VEGF and angiopoietin-1 gene transfer matures the new vasculature, reducing the vascular leakage seen in VEGF-induced capillaries.


CONCLUSIONS
These findings underscore the importance of the vasculature in what is traditionally thought of as an airway disease and open new therapeutic avenues for lung diseases characterized by irreversible loss of alveoli through the modulation of angiogenic growth factors.
Thébaud
Bernard
B
Division of Neonatology, Department of Pediatrics, University of Alberta, Edmonton, Canada. bthebaud@ualberta.ca
Ladha
Faruqa
F
Michelakis
Evangelos D
ED
Sawicka
Monika
M
Thurston
Gavin
G
Eaton
Farah
F
Hashimoto
Kyoko
K
Harry
Gwyneth
G
Haromy
Alois
A
Korbutt
Greg
G
Archer
Stephen L
SL
D000256:Adenoviridae; D000792:Angiography; D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000628:therapy*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000502:physiology / Q000648:ultrastructure; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D018496:Hyperoxia / Q000628:therapy*; D007231:Infant, Newborn; D008168:Lung / Q000098:blood supply*; D055370:Lung Injury; D018919:Neovascularization, Physiologic; D011650:Pulmonary Alveoli / Q000098:blood supply*; D011651:Pulmonary Artery; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000627:therapeutic use*
D042461:Vascular Endothelial Growth Factor A