Adaptability of skeletal muscle capillary supply and the potential for exercise-induced angiogenesis in cardiovascular disease

Exercise intolerance is prominent in diseases resulting in limb ischaemia. One characteristic is microvascular rarefaction that contributes to reduced skeletal muscle performance due to limited capillary perfusion and tissue oxygenation. Exercise training potentially stimulates capillary growth (angiogenesis), thus increasing muscle aerobic capacity, and in humans and rodents also changes fibre type towards a more oxidative phenotype. These physiological changes facilitate long periods of sustained physical work, but patients are often exercise-intolerant. Voluntary wheel running exercise (VWRE) imposes less stress on animals than other approaches, but little information is available about how this affects muscle performance and capillarity. Therefore, this thesis examines the effect of VWRE on muscle adaptation and how it may improve exercise capacity, using a comprehensive analytical approach. The first study showed increased muscle capillarity after 7-week VWRE, but activity peaked around 4 weeks. Next we found significant angiogenesis after 4 weeks VWRE accompanied by fibre hypertrophy. Optimising histological analysis for capillary markers and fibre type allowed aerobic capacity to be determined, and potential influence on muscle work quantified through oxygen transport modelling. A survey of muscles quantified inter-strain differences. The potential of exercise-induced angiogenesis for improving exercise intolerance in models of local (unilateral femoral artery ligation) and systemic (arterial stenosis) ischaemia were examined. While exercise had only a mild effect on capillarisation, it reversed impaired muscle performance in ligated (LRW) and aortic banded (ABRW) animals. The final study assessed peak aerobic capacity (V̇O2 peak) and running economy (RE) following endurance exercise. Both parameters were improved in VWRE rats due to improved musculoskeletal and cardiovascular systems, and that ABRW group enhanced V̇O2 peak while LRW group only improved RE. In conclusion, these studies provide additional insight into the role of angiogenesis in muscle performance restoration of ischaemic muscle and voluntary wheel running exercise as a therapeutic intervention.