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Am J Physiol Lung Cell Mol Physiol 283: L555-L562, 2002. First published April 19, 2002; doi:10.1152/ajplung.00408.2001
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Vol. 283, Issue 3, L555-L562, September 2002

Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structure

Timothy D. Le Cras1, Neil E. Markham1, Rubin M. Tuder2, Norbert F. Voelkel3, and Steven H. Abman1

Pediatric Heart Lung Center, 1 Departments of Pediatrics and 3 Medicine, University of Colorado School of Medicine, Denver, Colorado 80262; and 2 Department of Pathology, Johns Hopkins Medical Center, Baltimore, Maryland 21205

To determine whether disruption of vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) signaling in the newborn has long-term effects on lung structure and function, we injected 1-day-old newborn rat pups with a single dose of Su-5416, a VEGFR inhibitor, or vehicle (controls). Lungs from infant (3-wk-old) and adult (3- to 4-mo-old) rats treated with Su-5416 as newborns showed reductions in arterial density (82 and 31%, respectively) and alveolar counts (45 and 29%) compared with controls. Neonatal treatment with Su-5416 increased right ventricle weight to body wt ratios (4.2-fold and 2.0-fold) and pulmonary arterial wall thickness measurements (2.7-fold and 1.6-fold) in infant and adult rats, respectively, indicating marked pulmonary hypertension. We conclude that treatment of newborn rats with the VEGFR inhibitor Su-5416 impaired pulmonary vascular growth and postnatal alveolarization and caused pulmonary hypertension and that these effects were long term, persisting well into adulthood.

angiogenesis; postnatal lung development; alveogenesis; bronchopulmonary dysplasia; pulmonary vascular development; vascular endothelial growth factor


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