Inhibition of VEGF and Tie receptor signaling prevents exercise-induced angiogenesis, but only VEGF is required for the oxidative fiber type shift. (A) Voluntary mouse running model - mice ran 8-10 km per might when provided with running wheels, resulting in a 50% increase in capillary density (B). Systemic delivery of soluble VEGF receptor (sFlt) or soluble Tie2 (sTie2) as ligand traps significantly inhibited exercise-induced angiogenesis (B). In contrast, only blocking VEGF signaling with sFlt prevented the exercise-induced increase in oxidative metabolism, as measured by changes in oxidative type IIa fibers (C), PGC-1 mRNA (D), or citrate synthase activity (not shown).