Inhaled nitric oxide attenuates pulmonary hypertension and improves lung growth in infant rats after neonatal treatment with a VEGF receptor inhibitor

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 287; no. 2; pp. L344 - L351
• Main Authors: Tang, Jen-Ruey, Markham, Neil E, Lin, Yuh-Jyh, McMurtry, Ivan F, Maxey, Anne, Kinsella, John P, Abman, Steven H
• Format: Journal Article
• Language: English
• Published: United States 01.08.2004
• Subjects: Administration, Inhalation; Animals; Animals, Newborn; Bronchopulmonary Dysplasia - drug therapy; Enzyme Inhibitors - pharmacology; Female; Humans; Hypertension, Pulmonary - drug therapy; Indoles - pharmacology; Infant, Newborn; Nitric Oxide - pharmacology; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type III; Pregnancy; Pulmonary Alveoli - drug effects; Pulmonary Alveoli - growth & development; Pyrroles - pharmacology; Rats; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00291.2003

1 Pediatric Heart Lung Center and 3 Cardiovascular Pulmonary Research Laboratory, University of Colorado School of Medicine, Denver, Colorado 80218; and 2 Pediatrics, National Cheng-Kung University Hospital, Tainan, Taiwan 70101 Submitted 26 August 2003 ; accepted in final form 18 March 2004 VEGF plays a critical role during lung development and is decreased in human infants with bronchopulmonary dysplasia. 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 SU-5416 (a VEGF receptor inhibitor) or vehicle by subcutaneous injection and were killed up to 3 wk 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 SU-5416 increased RVH in infant rats and reduced RAC. Compared with controls, SU-5416 reduced lung eNOS protein expression by 89% at 5 days ( P < 0.01). IPL studies from day 14 rats demonstrated increased baseline pulmonary artery pressure and lower perfusate NOx concentration after SU-5416 treatment. Importantly, iNO treatment prevented the increase in RVH and improved RAC after SU-5416 treatment. We conclude that treatment of neonatal rats with SU-5416 downregulates lung eNOS expression and that iNO therapy decreases PH and improves lung growth after SU-5416 treatment. We speculate that decreased NO production contributes to PH and decreases distal lung growth caused by impaired VEGF signaling. vascular endothelial growth factor; bronchopulmonary dysplasia; lung development; alveolarization Address for reprint requests and other correspondence: S. H. Abman, Dept. of Pediatrics, B-395, Children's Hospital, 1056 E. 19th Ave., Denver, CO 80218-1088 (E-mail: steven.abman{at}uchsc.edu )