Developmental regulation of NO-mediated VEGF-induced effects in the lung.
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.
Bhandari
Vineet
V
Division of Perinatal Medicine, Yale University School of Medicine, Department of Pediatrics, New Haven, CT 06520-8057, USA. vineet.bhandari@yale.edu
Choo-Wing
Rayman
R
Lee
Chun G
CG
Yusuf
Kamran
K
Nedrelow
Jonathan H
JH
Ambalavanan
Namasivayam
N
Malkus
Herbert
H
Homer
Robert J
RJ
Elias
Jack A
JA
D000653:Amniotic Fluid / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002199:Capillary Permeability; D005260:Female; D006470:Hemorrhage / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018496:Hyperoxia / Q000378:metabolism / Q000473:pathology; D007231:Infant, Newborn; D008168:Lung / Q000098:blood supply / Q000254:growth & development / Q000378:metabolism*; D008171:Lung Diseases / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000502:physiology*; D011247:Pregnancy; D011663:Pulmonary Surfactants / Q000378:metabolism; D012127:Respiratory Distress Syndrome, Newborn / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D014132:Trachea / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
D011663:Pulmonary Surfactants; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide