Investigating the Role of the VEGF Heparin-Binding Domain in Mediating Accelerated Compensatory Lung Growth After Left Pneumonectomy
Lumeng J Yu1, Duy T Dao1, Victoria Ko1, Amy Pan1, Bennet S Cho1, Lorenzo Anez-Bustillos1, and Mark Puder1 1Dept. of Surgery, Vascular Biology Program, Boston Children’s Hospital, Boston, MA
Background:
Neonates with hypoplastic lung diseases may be deficient in vascular endothelial growth factor (VEGF). Previously, our group established that VEGF164 (human VEGF165), the most abundant VEGF isoform, enhances compensatory lung growth in animal preclinical studies, rendering it a promising therapy for pulmonary hypoplasia. In moving towards initiating human clinical trials, we investigate the mechanisms of VEGF164, postulating that its effect is dependent on the heparin-binding domain (HBD) of VEGF164.
Methods:
Human microvascular lung endothelial cells (HMVEC-L) were treated with VEGF121 (isoform lacking HBD; mouse VEGF120) or VEGF165, and VEGFR2 activation was determined by immunoblot. Eight-week old male C57Bl/6J mice underwent left pneumonectomy and were treated with intraperitoneal saline control, or VEGF120 at 0.5mg/kg or 1.0mg/kg. On post-operative day four, mice underwent pulmonary function tests and lung harvest for morphometric analysis. Endothelial proliferation was assessed via immunofluorescence staining with Ki-67 (proliferative marker) and ERG (endothelial cell marker).
Results:
VEGF121 treatment activated VEGFR2 in HMVEC-L, but less potently than VEGF165. 0.5mg/kg VEGF120 improved lung volume compared to saline control, although not statistically significant, with no further improvement at the 1.0mg/kg dose. There were no differences in total lung capacity, compliance, parenchymal volume, alveolar volume, septal surface area, mean septal thickness, or total alveolar count between VEGF120-treated mice and saline-treated controls. Endothelial cell proliferation in the lung was similar among VEGF120 versus saline-treated mice.
Conclusion:
The heparin-binding domain of VEGF is required for acceleration of compensatory lung growth, thus non-heparin binding isoforms of VEGF cannot be used as treatment in pulmonary hypoplasia.
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