title: Impaired collateral vessel development associated with reduced expression of vascular endothelial growth factor in ApoE-/- mice.
abstract: BACKGROUND
  The impact of disordered lipid metabolism on collateral vessel development was studied in apolipoprotein (apo)E-/- mice with unilateral hindlimb ischemia.
  
  
  RESULTS
  Hindlimb blood flow and capillary density were markedly reduced in apoE-/- mice versus C57 controls. This was associated with reduced expression of vascular endothelial growth factor (VEGF) in the ischemic limbs of apoE-/- mice. Cell-specific immunostaining localized VEGF protein expression to skeletal myocytes and infiltrating T cells in the ischemic limbs of C57 mice; in contrast, T-cell infiltrates in ischemic limbs of apoE-/- mice were severely reduced. The critical contribution of T cells to VEGF expression and collateral vessel growth was reinforced by the finding of accelerated limb necrosis in athymic nude mice with operatively induced hindlimb ischemia. Adenoviral VEGF gene transfer to apoE-/- mice resulted in marked augmentation of hindlimb blood flow and capillary density.
  
  
  CONCLUSIONS
  These findings thus underscore the extent to which hyperlipidemia adversely affects native collateral development but does not preclude augmented collateral vessel growth in response to exogenous cytokines. Moreover, results obtained in the apoE-/- and athymic nude mice imply a critical role for infiltrating T cells as a source of VEGF in neovascularization of ischemic tissues.
authors.affiliation: Department of Medicine, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Couffinhal
authors.forename: M
authors.initials: M
authors.lastname: Silver
authors.forename: M
authors.initials: M
authors.lastname: Kearney
authors.forename: A
authors.initials: A
authors.lastname: Sullivan
authors.forename: B
authors.initials: B
authors.lastname: Witzenbichler
authors.forename: M
authors.initials: M
authors.lastname: Magner
authors.forename: B
authors.initials: B
authors.lastname: Annex
authors.forename: K
authors.initials: K
authors.lastname: Peters
authors.forename: J M
authors.initials: JM
authors.lastname: Isner
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D001161:Arteriosclerosis / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D001783:Blood Flow Velocity; D003097:Collateral Circulation / Q000502:physiology*; D016228:Endothelial Growth Factors / Q000032:analysis / Q000235:genetics*; D005434:Flow Cytometry; D015870:Gene Expression / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology; D006949:Hyperlipidemias / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D017403:In Situ Hybridization; D007511:Ischemia / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D007763:Lac Operon; D018655:Lymphocyte Count; D008222:Lymphokines / Q000032:analysis / Q000235:genetics*; D008264:Macrophages / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D018482:Muscle, Skeletal / Q000098:blood supply / Q000737:chemistry; D009336:Necrosis; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D013601:T-Lymphocytes / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D014162:Transfection; D018608:Ultrasonography, Doppler; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D001057:Apolipoproteins E; D016228:Endothelial Growth Factors; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor