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

Thierry Couffinhal, Marcy Silver, Marianne Kearney, Alison Sullivan, Bernhard Witzenbichler, Meredith Magner, Brian Annex, Kevin Peters, Jeffrey M. Isner

Research output: Contribution to journalArticlepeer-review

244 Scopus citations

Abstract

Background - The impact of disordered lipid metabolism on collateral vessel development was studied in apolipoprotein (apo)E(-/-) mice with unilateral hindlimb ischemia. Methods and 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.

Original languageEnglish (US)
Pages (from-to)3188-3198
Number of pages11
JournalCirculation
Volume99
Issue number24
DOIs
StatePublished - Jun 22 1999
Externally publishedYes

Keywords

  • Angiogenesis
  • Apolipoproteins
  • Atherosclerosis
  • Collateral circulation
  • Growth substances

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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