title: VEGF₁₆₄ isoform specific regulation of T-cell-dependent experimental colitis in mice.
abstract: BACKGROUND
  Inflammatory bowel disease (IBD) consists of Crohn's disease (CD) and ulcerative colitis (UC), two widespread diseases of unknown, multifactorial etiology. Colitis pathology involves a pathological angiogenic response where increases in vascular density participate in colitis histopathology. Vascular endothelial growth factor-A (VEGF-A) is a potent angiogenesis stimulator known to be involved in pathological angiogenesis in several diseases including colitis. However, the pathogenic importance of specific VEGF-A isoforms during T-cell-mediated experimental colitis remains largely unknown.
  
  
  METHODS
  The CD4⁺ CD45RB(high) T-cell transfer model of experimental colitis was used for these studies. The VEGF lac-Z transgenic reporter mouse was used to examine specific cellular sources of VEGF-A production. The VEGF₁₆₄ aptamer (Macugen), adenoviral VEGF₁₆₄, and the VEGF Trap were used to evaluate pathological importance.
  
  
  RESULTS
  VEGF lac-Z reporter mice experiments showed that both infiltrating T cells and local tissue cells produce VEGF-A in the colon during disease. Inhibition of VEGF₁₆₄ using a highly selective RNA aptamer significantly attenuated CD4⁺ CD45RB(high) T-cell-dependent experimental colitis by reducing pathological angiogenesis and inflammatory pathology. Conversely, broad-spectrum VEGF inhibition with VEGF Trap did not attenuate disease, nor did adenoviral VEGF₁₆₄ overexpression significantly alter colitis pathology.
  
  
  CONCLUSIONS
  VEGF₁₆₄ is actively produced by multiple cell types during T-cell-mediated colitis. Importantly, specific inhibition of the VEGF₁₆₄ isoform during T-cell-mediated colitis dose-dependently attenuated disease progression, while broad-scale inhibition of all VEGF-A isoforms was not therapeutically beneficial.
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center - Shreveport, Shreveport, Louisiana, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Chidlow
authors.forename: John D
authors.initials: JD
authors.lastname: Glawe
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Pattillo
authors.forename: Sibile
authors.initials: S
authors.lastname: Pardue
authors.forename: Songlin
authors.initials: S
authors.lastname: Zhang
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Kevil
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003092:Colitis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D018398:Homeodomain Proteins; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D017493:Leukocyte Common Antigens / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D020033:Protein Isoforms; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*
chemical_list: D052157:Aptamers, Nucleotide; D018398:Homeodomain Proteins; D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C064658:RAG-1 protein; D017493:Leukocyte Common Antigens