Articles in PresS. Am J Physiol Lung Cell Mol Physiol (April 2, 2004). 10.1152/ajplung.00291.2003
FINAL ACCEPTED VERSION
LCMP-00291-2003.R2
Inhaled Nitric Oxide Attenuates Pulmonary Hypertension and Improves Lung Growth In Infant Rats After Neonatal Treatment with a VEGF Receptor Inhibitor
Jen-Ruey Tang1 MD Neil E Markham1 BS Yuh-Jyh Lin3 MD Ivan F McMurtry2 PhD Anne Maxey, BS John P Kinsella1 MD Steven H Abman1 MD
Pediatric Heart Lung Center and 2Cardiovascular Pulmonary Research Laboratory,
1
University of Colorado School of Medicine, Denver, Colorado, United States; and 3Pediatrics, National Cheng-Kung University Hospital, Tainan, Taiwan
Correspondence: Steven H. Abman, Dept. of Pediatrics, B-395, Children’s Hospital, 1056 East Nineteenth Ave., Denver, CO 80218-1088 (E-mail:
[email protected]; phone: 303-864-5821; fax: 303-837-2924)
Copyright © 2004 by the American Physiological Society.
ABSTRACT
LCMP-00291-2003.R2
VEGF plays a critical role during lung development and is decreased in human infants with BPD. Inhibition of VEGF receptors in the newborn rat decreases vascular growth and alveolarization, and causes pulmonary hypertension (PH). Nitric oxide (NO) is a downstream mediator of VEGF, but whether the effects of impaired VEGF signaling are due to decreased NO production is unknown. Therefore, we sought to determine whether impaired VEGF signaling downregulates endothelial NO synthase (eNOS) expression in the developing lung, and whether inhaled NO (iNO) decreases PH and improves lung growth after VEGF inhibition. Newborn rats received a single dose of SU5416 (a VEGF receptor inhibitor) or vehicle by subcutaneous injection, and were killed up to 3 weeks of age for assessments of right ventricular hypertrophy (RVH); radial alveolar counts (RAC), lung eNOS protein; and NOx production in isolated perfused lungs (IPL). Neonatal treatment with SU5416 increased RVH in infant rats and reduced RAC. In comparison with controls, SU5416 reduced lung eNOS protein expression by 89% at 5 days (p
