Impaired collateral vessel development associated with reduced expression of vascular endothelial growth factor in ApoE(-/-) mice

Background-The impact of disordered lipid metabolism on collateral vessel d evelopment was studied in apolipoprotein (apo)E-/- mice with unilateral hin dlimb ischemia. Methods and Results-Hindlimb blood flow and capillary density were markedly reduced in apoE(-/-) mice versus C57 controls. This was associated with re duced expression of vascular endothelial growth factor (VEGF) in the ischem ic limbs of apoE(-/-) mice. Cell-specific immunostaining localized VEGF pro tein expression to skeletal myocytes and infiltrating T cells in the ischem ic 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 resulte d in marked augmentation of hindlimb blood now and capillary density. Conclusions-These findings thus underscore the extent to which hyperlipidem ia adversely affects native collateral development but does not preclude au gmented collateral vessel growth in response to exogenous cytokines, Moreov er, results obtained in the apoE(-/-) and athymic nude mice imply a critica l role for infiltrating T cells as a source of VEGF in neovascularization o f ischemic tissues.