Adenoviral Gene Transfer With Soluble Vascular Endothelial Growth Factor Receptors Impairs Angiogenesis and Perfusion in a Murine Model of Hindlimb Ischemia

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 (10 ⁹ 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 Conclusions— Systemic, soluble receptor–mediated VEGF inhibition indicates an essential role for endogenous VEGF during postischemic angiogenesis and hindlimb perfusion.