VEGF ENHANCES PULMONARY VASCULOGENESIS AND DISRUPTS LUNG MORPHOGENESIS IN-VIVO

Vascular endothelial growth factor (VEGF) was expressed in developing respiratory epithelial cells under control of the promoter from the hu man surfactant protein C (SP-C) gene, SP-C-VEGF transgenic mice did no t survive after birth. When obtained by hysterectomy on embryonic day 15 (E15) or 17 (E17), abnormalities in the transgenic mice were confin ed to the lung and were correlated with the expression of transgene mR NA as revealed by in situ hybridization. On E15 and E17, marked abnorm alities in lung morphogenesis were observed in transgenic mice. Lungs consisted of large dilated tubules with increased peritubular vascular ity, The mRNA levels of the VEGF receptor, Flk-1, and the endothelial cell specific receptor tyrosine kinase, Tie-1, were increased in lung mesenchyme of the transgenic mice. The numbers of acinar tubules and t he abundance of mesenchyme were decreased. Endogenous VEGF mRNA was ex pressed in the respiratory epithelial cells of the developing lungs, a nd the levels of VEGF mRNA were increased in the SP-C-VEGF transgenic mice. Although the normal pattern of immunostaining for SP-C and Clara cell secretory protein (CCSP) indicated that epithelial cell differen tiation was relatively unaltered by the transgene, electron microscopi c analysis revealed a lack of alveolar Type I cell differentiation at E18. Expression of VEGF in the developing respiratory epithelium of tr ansgenic mice increased growth of the pulmonary blood vessels, disrupt ed branching morphogenesis of the lung and inhibited Type I cell diffe rentiation. (C) 1998 Wiley-Liss, Inc.