Inhibition of angiogenesis decreases alveolarization in the developing ratlung

To determine whether angiogenesis is necessary for normal alveolarization, we studied the effects of two antiangiogenic agents, thalidomide and fumagi llin, on alveolarization during a critical period of lung growth in infant rats. Newborn rats were treated with daily injections of fumagillin, thalid omide, or vehicle during the first 2 wk of life. Compared with control trea tment, fumagillin and thalidomide treatment reduced lung weight-to-body wei ght ratio and pulmonary arterial density by 20 and 36%, respectively, and r educed alveolarization by 22%. Because these drugs potentially have nonspec ific effects on lung growth, we also studied the effects of Su-5416, an inh ibitor of the vascular endothelial growth factor receptor known as kinase i nsert domain-containing receptor/fetal liver kinase (KDR/flk)-1. As observe d with the other antiangiogenic agents, Su-5416 treatment decreased alveola rization and arterial density. We conclude that treatment with three differ ent antiangiogenic agents attenuated lung vascular growth and reduced alveo larization in the infant rat. We speculate that angiogenesis is necessary f or alveolarization during normal lung development and that injury to the de veloping pulmonary circulation during a critical period of lung growth can contribute to lung hypoplasia.