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1Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229; and 2Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262
Submitted 14 February 2003 ; accepted in final form 30 July 2003
Pulmonary vascular disease plays a major role in morbidity and mortality in infant and adult lung diseases in which increased levels of transforming growth factor (TGF)-
and its receptor EGFR have been associated. The aim of this study was to determine whether overexpression of TGF- disrupts pulmonary vascular development and causes pulmonary hypertension. Lung-specific expression of TGF- in transgenic mice was driven with the human surfactant protein (SP)-C promoter. Pulmonary arteriograms and arterial counts show that pulmonary vascular development was severely disrupted in TGF- mice. TGF- mice developed severe pulmonary hypertension and vascular remodeling characterized by abnormally extensive muscularization of small pulmonary arteries. Pulmonary vascular development was significantly improved and pulmonary hypertension and vascular remodeling were prevented in bitransgenic mice expressing both TGF- and a dominant-negative mutant EGF receptor under the control of the SP-C promoter. Vascular endothelial growth factor (VEGF-A), an important angiogenic factor produced by the distal epithelium, was decreased in the lungs of TGF- adults and in the lungs of infant TGF- mice before detectable abnormalities in pulmonary vascular development. Hence, overexpression of TGF- caused severe pulmonary vascular disease, which was mediated through EGFR signaling in distal epithelial cells. Reductions in VEGF may contribute to the pathogenesis of pulmonary vascular disease in TGF- mice.
bronchopulmonary dysplasia; angiogenesis; epidermal growth factor receptor; vascular endothelial growth factor
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