Vascular Endothelial Growth Factor (VEGF) Accelerates Compensatory Lung Growth
Sang Lee MD1,2,*, Maromi K. Sakurai MD1,2, Danielle A. Arsenault BS1,2, Vania Nose MD3, Jay M. Wilson MD1, John V. Heymach MD PhD1,2, Mark Puder MD PhD1,2
1Department of Surgery, Children's Hospital Boston, Harvard Medical School; 2Vasculary Biology Program, Children's Hospital Boston, Harvard Medical School; 3Department of Pathology, Brigham and Women's Hospital, Harvard Medical School
Hypothesis: We hypothesize that compensatory lung growth after a unilateral pneumonectomy in a mouse model is in part angiogenesis-dependent and can be accelerated with vascular endothelial growth factor (VEGF), possibly establishing future therapy for impaired lung growth and development.
Methods: A left pneumonectomy was performed in mice and treated with the pro-angiogenic factor VEGF and compared to control animals (pneumonectomy alone). Lung volume to body weight ratio was used to measure compensatory growth. The lungs were analyzed using immunohistochemistry by CD31 staining for endothelial cells and by Terminal deoxynucleotidyl transferase biotin-dUTP Nick End Labeling (TUNEL) for apoptotic cells. Lung morphometry was also examined. Measured parameters were total lung, air space, and alveolar tissue volume, as well as total alveolar surface density.
Results: Normal compensatory lung growth was complete by post-operative day 10 and was associated with diffuse apoptosis of endothelial cells and pneumocytes. This process was accelerated by VEGF, such that growth was complete by post-operative day 4 with a similar apoptosis pattern. Morphometric analysis revealed no significant difference in alveolar surface density, volume of respiratory regions and volume of respiratory airspaces between sham-operated and animals undergoing pneumonectomy.
Conclusions: We propose that VEGF stimulates increased blood vessel growth, thereby increasing energy substrate availability to lung tissue and hastening tissue regeneration. The apparent termination event is a wave of apoptosis in both endothelial cells and pneumocytes at day 10 in the untreated and day 4 in VEGF-treated animals. Morphometric studies, which showed no significant difference in air space volume between groups, suggest that tissue growth is hyperplasia-mediated as opposed to hypertrophy- i.e. actual tissue regeneration rather than tissue “swelling.” Our data suggests that VEGF is a potential treatment for diseases of impaired lung growth and development, such as broncho-pulmonary dysplasia (BPD) and lung hypoplasia associated with congenital diaphragmatic hernia (CDH). By hastening lung growth, complications of prolonged mechanical ventilation may be avoided.
* - Presenting Author