Peripheral arterial disease is a chronic disease with significant cardiovascular risk. Patients with peripheral artery disease experience pain in leg muscles during walking which is only relieved by rest (intermittent claudication) (Stewart et al. 2002; Prior et al. 2004). The goal of treatment in patients is to improve quality of life by minimizing ischaemic symptoms and preventing progression to vascular occlusion. Therapeutic strategies, including exercise-based interventions and exercise training, have been reported to increase pain-free walking and quality of life in these patients (Stewart et al. 2002; Watson et al. 2008). Meta-analysis has shown that the greatest improvements in walking occur when exercise sessions are of at least 30 min in length and when these sessions occur a minimum of two times per week (Gardner & Poehlman, 1995). Thus, the effectiveness of exercise as a therapeutic intervention may be limited if ischaemic pain prevents patients from performing exercise of sufficient length and frequency. Interventions that ‘jumpstart’ the benefits of exercise training by reducing ischaemic pain during initial training bouts could enhance the overall effectiveness of exercise therapy. In a recent issue of The Journal of Physiology, Colleran et al. (2010) report that exercise training, in addition to contributing to remodelling of collateral-dependent arteries, promotes endothelial function and vasodilatory responsiveness. If the mechanism(s) by which exercise training enhances endothelial function in collateral-dependent arteries can be identified, therapeutic interventions could be designed to reduce ischaemia during initial bouts of exercise training, thereby increasing exercise duration and promoting adherence to training by reducing ischaemic pain. Studies involving experimental animal models of peripheral artery disease have demonstrated the presence of a collateral circuit capable of circumventing the vascular obstruction in the lower limb (Yang et al. 1996, 2008); the conductance of this circuit increases following occlusion of a primary hind limb artery. Exercise training has been shown to enhance blood flow through this collateral circuitry in animal models of occlusive artery disease (Yang et al. 1996, 2008). Improvements in collateral-dependent blood flow to hindlimb muscles that occur with exercise training in these occlusive models are accompanied by remodelling and enlargement of collateral vessels. Much of the functional improvement that occurs with exercise training in the occluded hindlimb has been attributed to enlargement of these collateral vessels, presumably stimulated by increases in shear stress during periods of activity (Prior et al. 2004); however, the ability of exercise to alter the reactivity of collateral vessels has remained relatively unexplored. Colleran et al. (2010) present results from a study in which vascular reactivity of collateral vessels from the occluded hindlimb was assessed following 3 weeks of exercise training. They report that exercise enhanced vasodilatory responses to both acetylcholine and flow in peripheral collateral arteries. Exercise training has been reported to enhance endothelium-dependent vasodilatation of skeletal muscle arteries and arterioles in the absence of occlusion (Spier et al. 2004). Colleran et al. (2010) have reported that exercise training increases endothelial reactivity in collateral-dependent arteries, even when assessed at a low intraluminal pressure of 45 cmH2O, approximating conditions present distal to an occlusion. These results suggest that exercise training provides a stimulus sufficient to alter endothelial function even under conditions of reduced intravascular pressure. Importantly, the exercise training-induced improvement in flow-induced vasodilatation of peripheral collateral arteries persisted even in the presence of blockade of both nitric oxide synthase and cyclooxygenase pathways, suggesting that an alternative pathway contributes to the exercise training-induced enhancement of endothelial function in collateral arteries. This differs from reports that implicate nitric oxide signalling as the primary target of exercise training in skeletal muscle arteries and arterioles (Spier et al. 2004). The results of the study by Colleran et al. (2010) indicate that for a complete understanding of the role played by collateral vessels in exercise-induced amelioration of hindlimb bloodflow, careful examination of endothelial signalling pathways must occur. Indeed, if these pathways are carefully evaluated, the benefits of exercise training could be augmented by combined therapy which enhances endothelial function of collateral-dependent vessels in patients that experience significant ischaemic pain during bouts of exercise. Therapeutic intervention targeting these endothelial pathways might also benefit patients who are unable to perform exercise due to overwhelming pain.
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Jan 1, 2019
Hua Zhang + 1
Open Access
