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1 Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
2 Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA
* To whom correspondence should be addressed. E-mail: tim.lecras{at}chmcc.org.
Pulmonary vascular disease plays a major role in morbidity and mortality in infant and adult lung diseases in which increased levels of 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 SP-C promoter. Pulmonary arteriograms and arterial counts showed 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 prevented in bitransgenic mice expressing both TGF- and a dominant negative mutant EGF receptor (EGFR-M) 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 prior to 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.
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