Vascular endothelial growth factor (VEGF), a specific mitogen for endothelial cells, induces vasculogenesis and angiogenesis in a variety of organs in vitro and in vivo. In order to assess the role of VEGF in vasculogenesis and morphogenesis of the fetal lung, we expressed VEGF under control of the promoter/enhancer element of human surfactant protein C (SPC) gene. Lack of surviving founder mice suggested that the SPC-VEGF transgene was lethal in the perinatal period. When obtained by hysterotomy on post coitum day 15 or 17, 5/21 pups bore the transgene. Abnormalities in the transgenic mice were confined to the lung. On fetal day 15, marked abnormalities of lung morphogenesis were observed. The lungs consisted of large dilated tubules with markedly increased peritubular vascularity. Prematurely dilated bronchial tubules were encircled by cells staining diffusely for α-smooth muscle actin. On fetal day 17, the airways of the transgenic mice were dilated. The number of terminal lung buds and the abundance of mesenchyme were decreased. Staining for SPC and CCSP indicated that epithelial cell differentiation was relatively unaltered by the transgene. Consistent with the role of VEGF in pulmonary vasculogenesis and morphogenesis, endogenous VEGF was localized by immunohistochemistry to the airway epithelial cells from embryonic day 11 to postnatal day 1 in control animals. On both day 15 and 17, staining for VEGF was also observed in the respiratory epithelium of transgenic mice.

In conclusion, expression of VEGF in the developing respiratory epithelium of transgenic mice caused increased growth of pulmonary blood vessels and enhanced their proximity to the developing airway epithelium, in turn, disrupting morphogenesis of terminal bronchioles and causing premature sacculation of lung tubules. These findings support the hypothesis that the ingrowth of pulmonary blood vessels in fetal lung development is mediated by VEGF and demonstrate the interaction between pulmonary vascular development and lung morphogenesis.