Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structure.
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.
Le Cras
Timothy D
TD
Departments of Pediatrics, University of Colorado School of Medicine, Denver 80262, USA. Tim.Lecras@CHMCC.org
Markham
Neil E
NE
Tuder
Rubin M
RM
Voelkel
Norbert F
NF
Abman
Steven H
SH
D000792:Angiography; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001724:Birth Weight / Q000187:drug effects; D002908:Chronic Disease; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology; D000860:Hypoxia / Q000150:complications; D007211:Indoles; D008168:Lung / Q000473:pathology; D011650:Pulmonary Alveoli / Q000473:pathology; D011651:Pulmonary Artery / Q000473:pathology; D011652:Pulmonary Circulation / Q000187:drug effects; D011758:Pyrroles; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor; D013312:Stress, Physiological / Q000209:etiology / Q000503:physiopathology
D007211:Indoles; D011758:Pyrroles; D017978:Receptors, Growth Factor; C116890:Semaxinib; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor