Inhibition of Pigment Epithelium-Derived Factor (PEDF) Augments Vascular Endothelial Growth Factor (VEGF)-Induced Recovery of Limb Perfusion after Ischemia in Klotho Mouse

PEDF is a highly effective endogenous inhibitor of angiogenesis. However, the pathophysiological role of PEDF in therapeutic angiogenesis in the setting of limb ischemia is not fully understood. In this study, we investigated whether inhibition of PEDF could augment vascular endothelial growth factor (VEGF)-induced therapeutic angiogenesis and blood flow recovery in ischemic hindlimbs of precocious-aging klotho mice. Adductor PEDF mRNA levels in nontreated mice were dramatically decreased at day 3 and 7 after ischemic surgery, whereas those in VEGF-treated mice were significantly increased after the surgery. VEGF treatment caused a progressive improvement of limb perfusion after induction of ischemia, which was augmented by the simultaneous treatment with anti-PEDF Ab. Further, PEDF administration was found to significantly impair the recovery of limb perfusion and post-ischemic angiogenesis in VEGF-treated mice. However, anti-PEDF Ab administration did not enhance the VEGF-induced increase in capillary number in ischemic adductor muscles. Our present study suggests that blockade of PEDF is a novel therapeutic strategy for limb ischemia, which could potentiate the beneficial effects of VEGF on therapeutic angiogenesis.