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(Circulation. 2005;112:2477-2486.)
© 2005 American Heart Association, Inc.

Vascular Medicine

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

Bernard Thébaud, MD, PhD; Faruqa Ladha, BSc; Evangelos D. Michelakis, MD; Monika Sawicka, BSc; Gavin Thurston, MD; Farah Eaton, BSc; Kyoko Hashimoto, BSc; Gwyneth Harry, MSc; Alois Haromy, BSc; Greg Korbutt, PhD; Stephen L. Archer, MD

From the Vascular Biology Research Group (B.T., F.L., E.D.M., M.S., F.E., K.H., G.H., A.H., S.L.A.), the Department of Pediatrics, Division of Neonatology (B.T.), the Department of Medicine (E.D.M., S.L.A.), the Surgical-Medical Research Institute (G.K.), and the Department of Physiology (S.L.A.), University of Alberta, Edmonton, Canada; and Regeneron Pharmaceuticals Inc, Tarrytown, NY (G.T.).

Correspondence to Dr Bernard Thébaud, MD, PhD, University of Alberta, HMRC 407, Edmonton, Alberta, T6G 2S2, Canada. E-mail bthebaud{at}ualberta.ca

Received February 8, 2005; revision received June 6, 2005; accepted July 5, 2005.

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.

Methods and 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.

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