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Developmental Regulation of NO-Mediated VEGF-Induced Effects in the Lung

¹ Division of Perinatal Medicine, Department of Pediatrics, ² Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, ⁴ Department of Laboratory Medicine, and ⁵ Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; and ³ Division of Neonatology, Department of Pediatrics, University of Alabama School of Medicine, Birmingham, Alabama

Correspondence and requests for reprints should be addressed to Vineet Bhandari, M.D., D.M., Division of Perinatal Medicine, Yale University School of Medicine, Department of Pediatrics, 333 Cedar St., LCI 401B, New Haven, CT 06520-8057. E-mail: vineet.bhandari{at}yale.edu

Vascular endothelial growth factor (VEGF) is known to have a pivotal role in lung development and in a variety of pathologic conditions in the adult lung. Our earlier studies have shown that NO is a critical mediator of VEGF-induced vascular and extravascular effects in the adult murine lung. As significant differences have been reported in the cytokine responses in the adult versus the neonatal lung, we hypothesized that there may be significant differences in VEGF-induced alterations in the developing as opposed to the mature lung. Furthermore, nitric oxide (NO) mediation of these VEGF-induced effects may be developmentally regulated. Using a novel externally regulatable lung-targeted transgenic murine model, we found that VEGF-induced pulmonary hemorrhage was mediated by NO-dependent mechanisms in adults and newborns. VEGF enhanced surfactant production in adults as well as increased surfactant and lung development in newborns, via an NO-independent mechanism. While the enhanced survival in hyperoxia in the adult was partly NO-dependent, there was enhanced hyperoxia-induced lung injury in the newborn. In addition, human amniotic fluid VEGF levels correlated positively with surfactant phospholipids. Tracheal aspirate VEGF levels had an initial spike, followed by a decline, and then a subsequent rise, in human neonates with an outcome of bronchopulmonary dysplasia or death. Our data show that VEGF can have injurious as well as potentially beneficial developmental effects, of which some are NO dependent, others NO independent. This opens up the possibility of selective manipulation of any VEGF-based intervention using NO inhibitors for maximal potential clinical benefit.

Key Words: vascular endothelial growth factor • nitric oxide • lung • surfactant

CLINICAL RELEVANCE This article provides improved understanding of the regulation of vascular endothelial growth factor–induced lung maturation and injury in the murine lung with supportive human data.