Changes in expression of vascular endothelial growth factor and its receptors in neonatal hypoxia-induced pulmonary hypertension.
Vascular endothelial growth factor (VEGF) is a potent mitogen with angiogenic and vasoactive properties. VEGF can bind to two types of receptors. VEGF receptor 2 (VEGFR2) is mainly responsible for the dilator response to VEGF through nitric oxide (NO) release, whereas VEGFR1 may sequestrate the ligand. We hypothesized that in neonatal hypoxia-induced pulmonary hypertension, VEGF vasodilation is reduced. The dilator response to VEGF was assessed in isolated perfused lung of 1-d-old piglets that were exposed to either normoxia or hypoxia (fraction of inspired oxygen 0.10) for 14 d. The plasma and pulmonary artery concentration of VEGF was measured by quantitative sandwich enzyme immunoassay in piglets that were exposed to either normoxia or hypoxia for 1, 3, 7, or 14 d. The expression of VEGFR1, VEGFR2, and endothelial NO synthase in pulmonary artery was measured in the same study groups using Western blot analysis. VEGF (10(-12)-10(-9) M) induces a dose-dependent relaxation in 14-d normoxic piglets, whereas vasodilation is abolished after 14 d of hypoxia. VEGF tissue concentration is increased by hypoxia. VEGFR1 expression is dramatically increased after 1, 3, and 7 d of hypoxia compared with normoxia and returns to normal afterward. VEGFR2 expression is reduced by hypoxia at 14 d. However, endothelial NO synthase expression is not affected by hypoxia compared with normoxia. In neonatal hypoxia-induced pulmonary hypertension, VEGF is increased, whereas vasodilation to VEGF is abolished. This reduced vasodilation may be due to decreased VEGFR2 expression. We speculate that sequestration by VEGFR1 may also limit, to some extent, the vascular protecting effect of VEGF, thus contributing to the pathophysiologic changes seen in neonatal hypoxia-induced pulmonary hypertension.
Nadeau
Sophie
S
Division of Newborn Medicine, Department of Pediatrics, Montreal Children's Hospital, McGill University, Montreal, Quebec, Canada H3H 1P3.
Baribeau
Johanne
J
Janvier
Annie
A
Perreault
Thérèse
T
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D003600:Cytosol / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D000860:Hypoxia / Q000378:metabolism; D008024:Ligands; D008168:Lung / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010477:Perfusion; D013552:Swine; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D008024:Ligands; D042461:Vascular Endothelial Growth Factor A; D014662:Vasoconstrictor Agents; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019001:Nitric Oxide Synthase; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D010100:Oxygen