title: Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice.
abstract: Respiratory distress syndrome (RDS) due to insufficient production of surfactant is a common and severe complication of preterm delivery. Here, we report that loss of the hypoxia-inducible transcription factor-2alpha (HIF-2alpha) caused fatal RDS in neonatal mice due to insufficient surfactant production by alveolar type 2 cells. VEGF, a target of HIF-2alpha, regulates fetal lung maturation: because VEGF levels in alveolar cells were reduced in HIF-2alpha-deficient fetuses; mice with a deficiency of the VEGF(164) and VEGF(188) isoforms or of the HIF-binding site in the VEGF promotor died of RDS; intrauterine delivery of anti-VEGF-receptor-2 antibodies caused RDS and VEGF stimulated production of surfactant proteins by cultured type 2 pneumocytes. Intrauterine delivery or postnatal intratracheal instillation of VEGF stimulated conversion of glycogen to surfactant and protected preterm mice against RDS. The pneumotrophic effect of VEGF may have therapeutic potential for lung maturation in preterm infants.
authors.affiliation: The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity, Institute for Biotechnology, Leuven, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Compernolle
authors.forename: Koen
authors.initials: K
authors.lastname: Brusselmans
authors.forename: Till
authors.initials: T
authors.lastname: Acker
authors.forename: Peter
authors.initials: P
authors.lastname: Hoet
authors.forename: Marc
authors.initials: M
authors.lastname: Tjwa
authors.forename: Heike
authors.initials: H
authors.lastname: Beck
authors.forename: Stéphane
authors.initials: S
authors.lastname: Plaisance
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
authors.forename: Eli
authors.initials: E
authors.lastname: Keshet
authors.forename: Florea
authors.initials: F
authors.lastname: Lupu
authors.forename: Benoit
authors.initials: B
authors.lastname: Nemery
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.forename: Paul
authors.initials: P
authors.lastname: Van Veldhoven
authors.forename: Karl
authors.initials: K
authors.lastname: Plate
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.forename: Désiré
authors.initials: D
authors.lastname: Collen
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000375:Aging; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000494:pharmacology / Q000502:physiology*; D008168:Lung / Q000187:drug effects / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D008171:Lung Diseases / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008222:Lymphokines / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000254:growth & development / Q000473:pathology; D012128:Respiratory Distress Syndrome / Q000473:pathology; D020545:Respiratory Mucosa / Q000473:pathology / Q000503:physiopathology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1