title: Mesenchymal-specific inhibition of vascular endothelial growth factor (VEGF) attenuates growth in neonatal mice.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis and vasculogenesis. However, the role of VEGF in the regulation of neonatal mouse development is not completely defined. We sought to determine the effect of VEGF inhibition on the development of the neonatal mouse using a transgenic approach.
  
  
  METHODS
  We generated triple transgenic mice that express the soluble VEGF receptor, (sFlt-1), specifically in the mesenchyme (dermo-1(Cre)- tetracycline reverse transcriptional activator (rtTA)(flox/flox)-tet(0)-sflt-1). Mothers of the pups (transgenic and littermate controls) were fed doxycycline chow at birth for transgene activation via breast milk, and the pups were sacrificed at various time points. To test reversibility of the phenotype, mice from both groups (n = 6) were switched to normal chow at P50 and monthly weights were measured for 9 mo.
  
  
  RESULTS
  Dermo-1(Cre)-rtTA(flox/flox)-tet(0)-sflt-1 mice were smaller compared with littermate controls at P21. There was a significant reduction in tissue VEGF levels following sFlt-1 expression. The rate of growth was reduced but did not impact overall survival after 1 y. A significant reduction in organ size as a percentage body weight was seen in the kidney and stomach, whereas the weight of the colon and spleen were relatively increased; however, no gross histologic difference was observed. After 6 mo on normal diet, the dermo-1(Cre)-rtTA(flox/flox)-tet(0)-sflt-1 mouse's weight doubled, indicating reversibility of phenotype.
  
  
  CONCLUSIONS
  Mesenchymal-specific inhibition of VEGF in neonatal mice results in a severe but reversible arrest in somatic growth that does not affect overall survival at 1 yr. This mouse is a useful tool to test the function of VEGF in somatic growth.
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA.
authors.forename: Jamil A
authors.initials: JA
authors.lastname: Matthews
authors.forename: Frédéric G
authors.initials: FG
authors.lastname: Sala
authors.forename: Allison L
authors.initials: AL
authors.lastname: Speer
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Warburton
authors.forename: Tracy C
authors.initials: TC
authors.lastname: Grikscheit
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development*; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D005260:Female; D048788:Growth and Development / Q000502:physiology*; D008297:Male; D008648:Mesoderm / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D009929:Organ Size / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D048348:Reverse Transcription / Q000235:genetics / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000502:physiology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000502:physiology
chemical_list: D012097:Repressor Proteins; D015534:Trans-Activators; D051879:Twist-Related Protein 1; C096852:Twist2 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1