Developmental regulation of NO-mediated VEGF-induced effects in the lung.

Academic Article

Abstract

  • 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.
  • Keywords

  • Amniotic Fluid, Animals, Animals, Newborn, Bronchopulmonary Dysplasia, Capillary Permeability, Female, Hemorrhage, Humans, Hyperoxia, Infant, Newborn, Lung, Lung Diseases, Mice, Mice, Transgenic, Nitric Oxide, Pregnancy, Pulmonary Surfactants, Respiratory Distress Syndrome, Newborn, Trachea, Vascular Endothelial Growth Factor A
  • Digital Object Identifier (doi)

    Author List

  • Bhandari V; Choo-Wing R; Lee CG; Yusuf K; Nedrelow JH; Ambalavanan N; Malkus H; Homer RJ; Elias JA
  • Start Page

  • 420
  • End Page

  • 430
  • Volume

  • 39
  • Issue

  • 4