Chronic hypoxia attenuates resting and exercise-induced VEGF, fit-1, and flk-1 mRNA levels in skeletal muscle

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible angiogenic mitogen. However, chronic hypoxia is generally not found to increase mamma lian skeletal muscle capillarity. We sought to determine the effect of chro nic hypoxia (8 wk, inspired O-2 fraction = 0.12) on skeletal muscle gene ex pression of VEGF, its receptors (flt-1 and flk-1), basic fibroblast growth factor, and transforming growth factor-beta (1). Wistar rats were exposed t o chronic hypoxia (n = 12) or room air (n = 12). After the exposure period, six animals from each group were subjected to a single l-h treadmill exerc ise bout (18 m/min on a 10 degrees incline) in room air while the remaining six animals served as rest controls. Morphological analysis revealed that chronic hypoxia did not increase skeletal muscle capillarity. Northern blot analyses showed that chronic hypoxia decreased resting VEGF, flt-1, and fl k-1 mRNA by 23, 68, and 42%, respectively (P < 0.05). The VEGF mRNA respons e to exercise was also decreased (4.1- and 2.7-fold increase in room air an d chronic hypoxia, respectively, P < 0.05). In contrast, neither transformi ng growth factor-beta (1) nor basic fibroblast growth factor mRNA was signi ficantly altered by chronic hypoxia. In conclusion, prolonged exposure to h ypoxia attenuated gene expression of VEGF and its receptors flt-1 and flk-1 in rat gastrocnemius muscle. These findings may provide an explanation for the lack of mammalian skeletal muscle angiogenesis that is observed after chronic hypoxia.