HIF and VEGF relationships in response to hypoxia and sciatic nerve stimulation in rat gastrocnemius

To determine if hypoxia-inducible factor-1 (HIF-1) may regulate skeletal muscle vascular endothelial growth factor (VEGF) expression in response to exercise or hypoxia, rats underwent 1 h sciatic nerve electrical stimulation (ES), hypoxic exposure (H) or combined stimuli. HIF-1α protein levels increased six-fold with maximal (8 V) ES with or without H. Similar HIF-1α increases occurred with sub-maximal (6 V and 4 V) ES plus H, but not in sub-maximal ES or H alone. VEGF mRNA and protein levels increased three-fold in sub-maximal ES or H alone, six-fold in sub-maximal ES plus H, 6.3-fold with maximal ES, and 6.5-fold after maximal ES plus H. These data suggest: (1) intracellular hypoxia during normoxic exercise may exceed that during 8% oxygen breathing at rest and is more effective in stimulating HIF-1α; (2) HIF-1 may be an important regulator of exercise-induced VEGF transcription; and (3) breathing 8% O₂ does not alter HIF-1α expression in skeletal muscle, implying that exercise-generated signals contribute to the regulation of HIF-1α and/or VEGF.