Inhibition of angiogenesis decreases alveolarization in the developing rat lung.
To determine whether angiogenesis is necessary for normal alveolarization, we studied the effects of two antiangiogenic agents, thalidomide and fumagillin, on alveolarization during a critical period of lung growth in infant rats. Newborn rats were treated with daily injections of fumagillin, thalidomide, or vehicle during the first 2 wk of life. Compared with control treatment, fumagillin and thalidomide treatment reduced lung weight-to-body weight ratio and pulmonary arterial density by 20 and 36%, respectively, and reduced alveolarization by 22%. Because these drugs potentially have nonspecific effects on lung growth, we also studied the effects of Su-5416, an inhibitor of the vascular endothelial growth factor receptor known as kinase insert domain-containing receptor/fetal liver kinase (KDR/flk)-1. As observed with the other antiangiogenic agents, Su-5416 treatment decreased alveolarization and arterial density. We conclude that treatment with three different antiangiogenic agents attenuated lung vascular growth and reduced alveolarization in the infant rat. We speculate that angiogenesis is necessary for alveolarization during normal lung development and that injury to the developing pulmonary circulation during a critical period of lung growth can contribute to lung hypoplasia.
Jakkula
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M
Pediatric Pulmonary Medicine, Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado 80218, USA.
Le Cras
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Gebb
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Hirth
K P
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Tuder
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Voelkel
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Abman
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D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development*; D001466:Barium Sulfate / Q000008:administration & dosage; D001835:Body Weight / Q000187:drug effects; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005780:Gelatin / Q000008:administration & dosage; D006321:Heart / Q000033:anatomy & histology; D007211:Indoles / Q000494:pharmacology; D007269:Injections, Intra-Arterial; D008168:Lung / Q000033:anatomy & histology / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009929:Organ Size / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000033:anatomy & histology / Q000187:drug effects / Q000254:growth & development*; D011651:Pulmonary Artery / Q000033:anatomy & histology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor; D012717:Sesquiterpenes; D013792:Thalidomide / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D007211:Indoles; D011758:Pyrroles; D017978:Receptors, Growth Factor; D012717:Sesquiterpenes; D001466:Barium Sulfate; D013792:Thalidomide; C116890:Semaxinib; C026211:fumagillin; D005780:Gelatin; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor