Adenoviral gene transfer with soluble vascular endothelial growth factor receptors impairs angiogenesis and perfusion in a murine model of hindlimb ischemia

Johannes Jacobi, Betty Y.Y. Tam, Grace Wu, Jana Hoffman, John P. Cooke, Calvin J. Kuo

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

Background - The purpose of the current study was to examine the contribution of endogenous vascular endothelial growth factor (VEGF) to ischemia-induced angiogenesis and perfusion. Methods and Results - C57BL/6J mice (n=28) were subjected to unilateral hindlimb ischemia after intravenous injection of recombinant adenoviruses (109 plaque-forming units) encoding the ligand-binding ectodomain of VEGF receptor 1 (VEGFR1/Ad Flt1), VEGF receptor 2 (VEGFR2/Ad Flk1-Fc), a control murine IgG2α Fc fragment (Ad Fc), or vehicle (phosphate-buffered saline). Hindlimb perfusion was assessed by both laser Doppler and fluorescent microsphere injection 10 days after surgery. The role of endogenous VEGF in ischemia-induced angiogenesis and arteriogenesis was measured by capillary density and microangiography, respectively. Adenoviral gene transfer with soluble VEGFRs significantly attenuated hindlimb perfusion as assessed by laser Doppler and microsphere analysis (P<0.05). Furthermore, soluble VEGFRs significantly reduced ischemia-induced angiogenesis and collateral growth and inhibited histological recovery of muscle tissue. Adverse events consistent with ongoing vascular insufficiency such as limb necrosis or gangrene were observed only in animals expressing soluble VEGFRs and not in control animals. Conclusions - Systemic, soluble receptor-mediated VEGF inhibition indicates an essential role for endogenous VEGF during postischemic angiogenesis and hindlimb perfusion.

Original languageEnglish (US)
Pages (from-to)2424-2429
Number of pages6
JournalCirculation
Volume110
Issue number16
DOIs
StatePublished - Oct 19 2004

Keywords

  • Angiogenesis
  • Collateral circulation
  • Genetics
  • Ischemia
  • Perfusion

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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