Exercise training is well recognised as an effective treatment for intermittent claudication. The mechanism underlying exercise induced improvements is multi-factorial but remains poorly understood. Low angiotensin-converting enzyme (ACE) activity has been associated with enhanced responses to endurance training. Specifically, low ACE activity has been associated with improved muscle metabolism, endothelial function, and suppressed inflammatory responses; processes linked with exercise training benefits in claudicants. Furthermore, pharmacological inhibition of ACE has been associated with enhanced angiogenesis in animal models of ischaemia, secondary to increases in vascular endothelial growth factor (VEGF). In this study, 11 claudicants were randomised to 8 weeks of supervised exercise training (n=6) or exercise advice (n=5). Walking ability was recorded before and after this period, and blood samples taken. Reverse transcription polymerase chain reaction (RT-PCR) was used to determine the effects of exercise training on ACE, VEGF and VEGF receptor (VEGFR) gene expression, and enzyme-linked immunosorbant assays (ELISA) measured changes in ACE and VEGF protein levels. In another experiment, a cell culture model of hypoxia, utilising ECV 304 cells and diethylenetriamine-nitric oxide (DETA-NO), was used to study the effects of the ACE inhibitor ramiprilat on ACE and VEGF responses to hypoxia, using RT-PCR and ELISA. Supervised exercise improved claudication distance by 105 metres (p < 0.05) and maximum walking distance by 141 metres (p < 0.05). ACE mRNA expression increased 30%, VEGF121 expression 43% and VEGF165 expression 70% (all p < 0.05). Soluble VEGFR-1 mRNA expression increased by 63% and VEGFR-2 72% (both p < 0.05). ACE and VEGF protein levels remained comparatively stable. In the cell culture experiments, ramiprilat increased VEGF protein levels in hypoxia. Although a lack of experimental runs prevented statistical analysis, the results also suggest that ramiprilat has a stimulatory effect on ACE mRNA expression in hypoxia. Improvements in walking ability after exercise training are associated with increases in both VEGF and VEGF receptor expression. ACE inhibitors could play a role in improving claudication by potentiating increases in VEGF in addition to their known action of suppressing ACE activity
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