Patients with chronic renal failure (CRF) have impaired exercise capacity even after erythropoietin treatment. We recently showed that although this is explained in part by reduced convective O(2) delivery to muscles, there is also an impairment of O(2) transport from muscle capillaries to the mitochondria. Given the importance of the capillary surface area for capillary mitochondrial O(2) transport and reports of reduced capillarity in CRF, we hypothesized that the angiogenic gene response to exercise is impaired in such patients. Six patients with CRF and six control subjects matched for age, size, and sedentary lifestyle exercised on a single occasion for 1 h at similar work intensities averaging 50% of maximal capacity. Exercise was confined to the knee extensors of a single leg by means of a specially designed leg-kick ergometer. A percutaneous biopsy of the quadriceps was taken within 30 min of cessation of exercise and compared with a similar biopsy done at different times without any prior exercise for 24 h. Conventional Northern blots were prepared and probed for vascular endothelial growth factor (VEGF; the major putative angiogenic growth factor for muscle), basic fibroblast growth factor (bFGF), and transforming growth factor (TGF)-beta(1). Data during both rest and exercise were successfully obtained in four subjects of each group. We also assessed muscle capillarity and mitochondrial oxidative capacity to relate to these changes. Mitochondrial oxidative capacity was normal, whereas capillary number per fiber was 12% lower than in normal subjects. VEGF mRNA abundance was increased after exercise by about one order of magnitude, with no reduction in response in CRF. For bFGF and TGF-beta(1), exercise elicited no response in either group. Reduced muscle capillarity in CRF does not, therefore, stem from reduced transcription of VEGF. To the extent that VEGF is important to exercise-induced angiogenesis in muscle, we suspect a posttranscriptional aberration in this response occurs in CRF to explain reduced capillarity.