title: Pigment epithelium-derived factor mediates impaired lung vascular development in neonatal hyperoxia.
abstract: Bronchopulmonary dysplasia is a chronic lung disease of preterm infants characterized by arrested microvascularization and alveolarization. Studies show the importance of proangiogenic factors for alveolarization, but the importance of antiangiogenic factors is unknown. We proposed that hyperoxia increases the potent angiostatin, pigment epithelium-derived factor (PEDF), in neonatal lungs, inhibiting alveolarization and microvascularization. Wild-type (WT) and PEDF(-/-) mice were exposed to room air (RA) or 0.9 fraction of inspired oxygen from Postnatal Day 5 to 13. PEDF protein was increased in hyperoxic lungs compared with RA-exposed lungs (P < 0.05). In situ hybridization and immunofluorescence identified PEDF production primarily in alveolar epithelium. Hyperoxia reduced alveolarization in WT mice (P < 0.05) but not in PEDF(-/-) mice. WT hyperoxic mice had fewer platelet endothelial cell adhesion molecule (PECAM)-positive cells per alveolus (1.4 ± 0.4) than RA-exposed mice (4.3 ± 0.3; P < 0.05); this reduction was absent in hyperoxic PEDF(-/-) mice. The interactive regulation of lung microvascularization by vascular endothelial growth factor and PEDF was studied in vitro using MFLM-91U cells, a fetal mouse lung endothelial cell line. Vascular endothelial growth factor stimulation of proliferation, migration, and capillary tube formation was inhibited by PEDF. MFLM-91U cells exposed to conditioned medium (CM) from E17 fetal mouse lung type II (T2) cells cultured in 0.9 fraction of inspired oxygen formed fewer capillary tubes than CM from T2 cells cultured in RA (hyperoxia CM, 51 ± 10% of RA CM, P < 0.05), an effect abolished by PEDF antibody. We conclude that PEDF mediates reduced vasculogenesis and alveolarization in neonatal hyperoxia. Bronchopulmonary dysplasia likely results from an altered balance between pro- and antiangiogenic factors.
authors: 1 Department of Pediatrics, Tufts Medical Center, Boston, Massachusetts.
authors: Anne
authors: A
authors: Chetty
authors: Michelle
authors: M
authors: Bennett
authors: Linh
authors: L
authors: Dang
authors: Daisy
authors: D
authors: Nakamura
authors: Gong-Jie
authors: GJ
authors: Cao
authors: Sana
authors: S
authors: Mujahid
authors: MaryAnn
authors: M
authors: Volpe
authors: Ira
authors: I
authors: Herman
authors: S Patricia
authors: SP
authors: Becerra
authors: Heber C
authors: HC
authors: Nielsen
mesh_terms: D043168:Angiostatins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D001997:Bronchopulmonary Dysplasia / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism*; D005136:Eye Proteins / Q000378:metabolism*; D018496:Hyperoxia / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D015843:Serpins / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D043168:Angiostatins; D005136:Eye Proteins; D009414:Nerve Growth Factors; D010100:Oxygen; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D015843:Serpins; D042442:Vascular Endothelial Growth Factors; D000099174:Pigment Epithelium-Derived Factor
keywords: angiogenesis; bronchopulmonary dysplasia; pigment epithelium–derived factor; vascular endothelial growth factor