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
Abstract
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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Such VEGF upregulation may have important clinical implications since VEGF and Ang-1 have been shown to play pivotal roles in angiogenesis, alveolar development, and treatment of acute lung injury (ALI).
“Such upregulation may have important clinical implications since VEGF and Ang-1 have been shown to play pivotal roles in angiogenesis, alveolar development, and treatment of acute lung injury (ALI) [8, 57–60].”
From Short-term physiological hypoxia potentiates the therapeutic function of mesenchymal stem cells (2018) · cites this paper as [57]
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- Authors
- Thébaud, B., Ladha, F., Michelakis, E. D., Sawicka, M., Thurston, G., Eaton, F., Hashimoto, K., Harry, G., Haromy, A., Korbutt, G., & Archer, S. L.
- Affiliations
- 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.).
- University of Alberta (CA)
- ORCID
- Venue
- Circulation
- Published
- 2005-10-18
- Volume
- 112
- Issue
- 16
- Pages
- 2477-2486
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2120215146
- Cited by
- 533
- References
- 53
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 16 · 2023: 16 · 2022: 14 · 2021: 44 · 2020: 36 · 2019: 25 · 2018: 26 · 2017: 23 · 2016: 36 · 2015: 31 · 2014: 37 · 2013: 38 · 2012: 30
- FWCI
- 15.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- Stollery Children’s Hospital Foundation
- Children's Hospital Foundation
- Fondation pour la Recherche Médicale
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL071115)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Neonatal Respiratory Health Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
- Keywords
- vascular endothelial growth factor, VEGF gene therapy, VEGFR2, bronchopulmonary dysplasia, hyperoxia-induced lung injury, alveolar development, alveolar damage, angiopoietin-1, adenoviral gene transfer, vascular leakage, neonatal rats
- MeSH terms
- Adenoviridae, Angiography, Animals, Animals, Newborn, Bronchopulmonary Dysplasia, Disease Models, Animal, Endothelium, Vascular, Genetic Vectors, Humans, Infant, Newborn, Lung, Pulmonary Alveoli, Pulmonary Artery, Genetic Therapy, Hyperoxia, Neovascularization, Physiologic, Vascular Endothelial Growth Factor A, Rats, Lung Injury
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