title: Sequestration of Vascular Endothelial Growth Factor (VEGF) Induces Late Restrictive Lung Disease.
abstract: BACKGROUND
  Neonatal respiratory distress syndrome is a restrictive lung disease characterized by surfactant deficiency. Decreased vascular endothelial growth factor (VEGF), which demonstrates important roles in angiogenesis and vasculogenesis, has been implicated in the pathogenesis of restrictive lung diseases. Current animal models investigating VEGF in the etiology and outcomes of RDS require premature delivery, hypoxia, anatomically or temporally limited inhibition, or other supplemental interventions. Consequently, little is known about the isolated effects of chronic VEGF inhibition, started at birth, on subsequent developing lung structure and function.
  
  
  OBJECTIVE
  To determine whether inducible, mesenchyme-specific VEGF inhibition in the neonatal mouse lung results in long-term modulation of AECII and whole lung function.
  
  
  METHODS
  Triple transgenic mice expressing the soluble VEGF receptor sFlt-1 specifically in the mesenchyme (Dermo-1/rtTA/sFlt-1) were generated and compared to littermate controls at 3 months to determine the impact of neonatal downregulation of mesenchymal VEGF expression on lung structure, cell composition and function. Reduced tissue VEGF bioavailability has previously been demonstrated with this model.
  
  
  RESULTS
  Triple transgenic mice demonstrated restrictive lung pathology. No differences in gross vascular development or protein levels of vascular endothelial markers was noted, but there was a significant decrease in perivascular smooth muscle and type I collagen. Mutants had decreased expression levels of surfactant protein C and hypoxia inducible factor 1-alpha without a difference in number of type II pneumocytes.
  
  
  CONCLUSIONS
  These data show that mesenchyme-specific inhibition of VEGF in neonatal mice results in late restrictive disease, making this transgenic mouse a novel model for future investigations on the consequences of neonatal RDS and potential interventions.
authors: Division of Pediatric Surgery, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States of America.
authors: Minna M
authors: MM
authors: Wieck
authors: Division of Pediatric Surgery, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States of America.
authors: Ryan G
authors: RG
authors: Spurrier
authors: Division of Pediatric Surgery, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States of America.
authors: Daniel E
authors: DE
authors: Levin
authors: Division of Pediatric Surgery, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States of America.
authors: Salvador Garcia
authors: SG
authors: Mojica
authors: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States of America.
authors: Michael J
authors: MJ
authors: Hiatt
authors: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States of America.
authors: Raghava
authors: R
authors: Reddy
authors: Division of Pediatric Surgery, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States of America.
authors: Xiaogang
authors: X
authors: Hou
authors: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States of America.|Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California, United States of America.
authors: Sonia
authors: S
authors: Navarro
authors: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States of America.
authors: Jooeun
authors: J
authors: Lee
authors: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States of America.
authors: Amber
authors: A
authors: Lundin
authors: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States of America.|Integrative Biology of Disease Graduate Program, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Barbara
authors: B
authors: Driscoll
authors: Division of Pediatric Surgery, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States of America.|Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States of America.
authors: Tracy C
authors: TC
authors: Grikscheit
mesh_terms: D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D003094:Collagen / Q000737:chemistry; D005260:Female; D005786:Gene Expression Regulation; D006909:Hydroxyproline / Q000737:chemistry; D016014:Linear Models; D008168:Lung / Q000254:growth & development* / Q000378:metabolism*; D008171:Lung Diseases / Q000378:metabolism*; D008297:Male; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D016133:Polymerase Chain Reaction; D012129:Respiratory Function Tests; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D003094:Collagen; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D006909:Hydroxyproline