Vascular endothelial growth factor-A induces prenatal neovascularization and alters bronchial development in mice

Pulmonary vascular development requires precise temporal and spatial expression of vascular endothelial growth factor-A (VEGF-A). Diminished expression of VEGF-A in preterm infants may contribute to the pathophysiology of respiratory distress syndrome. Because exogenous replacement of VEGF-A has been proposed as a therapeutic for respiratory distress syndrome, we used conditional activation of VEGF-A in bronchial epithelial cells to assess the effects of increase of VEGF-A on lung morphogenesis and survival in the developing mouse. Increased expression of VEGF-A in late stages of gestation was lethal at birth. Although born alive, the pups remained cyanotic and failed to establish respiration. Vascular and epithelial morphology of the main bronchus and primary and secondary bronchi were altered with neovascularization of the mucosal folds and partial obstruction of the conducting airways. Erythrocytes were observed in the pulmonary interstitium and in intra-alveolar spaces, indicating vascular leak. Increased diameter of pulmonary arteries and angioectatic structures were observed in VEGF-expressing mice. Bronchial expression of VEGF-A alters late-stage morphogenesis of conducting airways and primary bronchial arteries and causes respiratory failure at birth.