Exercise Prior to Lower Extremity Peripheral Artery Disease Improves Endurance Capacity and Hindlimb Blood Flow by Inhibiting Muscle Inflammation

Abstract

Lower extremity peripheral artery disease (PAD) is associated with functional decline. Physical exercise has been proven to be an effective therapeutic strategy for PAD; however the effect of exercise initiated before PAD remains unknown. Here, we investigated the preventive effects of exercise on endurance capacity, hindlimb perfusion, and on polarization profile of circulating monocytes and limb muscle macrophages. ApoE−/− mice were subjected to 5-week running wheel exercise or remained sedentary before induction of hindlimb ischemia. The two groups were thereafter kept sedentary. Exercised mice prior to PAD showed higher exhaustive treadmill running distance and time than sedentary mice. Preventive exercise also increased perfusion, arteriole density, and muscle regeneration in the ischemic hindlimb. Moreover, preventive exercise prevented ischemia-induced increased gene expression of pro-inflammatory M1 macrophages markers and cytokines in the ischemic muscle, while no changes were observed for anti-inflammatory M2 macrophage markers. Flow cytometry analysis showed that the proportion of circulating pro-inflammatory monocyte subtype decreased whereas that of anti-inflammatory monocytes increased with preventive exercise. Overall, we show that exercise initiated before PAD improves endurance performance and hindlimb perfusion in mice probably via inhibition of M1 macrophage polarization and inflammation in the ischemic muscle. Our study provides experimental evidence for a role of regular exercise in primary prevention of PAD.

Inflammatory and Prothrombotic Biomarkers, DNA Polymorphisms, MicroRNAs and Personalized Medicine for Patients with Peripheral Arterial Disease

“…Patients with PAD regularly experience ischemia of the tissue distant to arterial occlusions during exercise. The transient exercise-induced leg ischemia is related to increased release of inflammatory markers [ 42 ] and impairs vasodilator function of distant arteries in correlation with increased circulatory levels of interleukins, particularly IL-6 [ 43 ]. This could be one of the reasons that because of repeated ischemia-related release of inflammatory markers, PAD patients experience advanced systemic atherosclerosis including coronary heart disease (CHD) and other CV disease (CVD).…”

“…In contrast to the acute deleterious effects of ischemia, regular moderate exercise training not only improves walking capacity but also decreases vascular and inflammatory biomarkers [ 44 ]. Chronic exercise improves anti-oxidant capacity and decreases inflammatory response without increasing oxidative stress in symptomatic PAD patients [ 42 , 44 ]. Acute exercise usually leads to robust inflammatory response mainly characterized by the mobilization of leukocytes and an increase in circulating inflammatory mediators produced by immune cells and directly from active muscle tissue [ 44 ].…”

Research trends and hotspots of exercise therapy in Panvascular disease: A bibliometric analysis

“…After exercise, the macrophage marker, the number of arterioles, the number of regenerating myofibers, the percentage of anti-inflammatory monocytes, the expression of pro-arteriogenic genes, and myogenesis-related genes and quiescent satellite cells expressed the transcription factor were all increased in the ischemic muscle of mice, along with the percentage of pro-inflammatory monocytes and the levels of M1 macrophage markers nitric oxide synthase and IL-6 were decreased. [ 49 ] These findings provided new insights into the role of exercise in Panvascular disease. Neurons, nitric oxide, and oxidative stress were the hotspots of research on the mechanisms of exercise intervention in Panvascular disease identified by Citespace analysis.…”

The Role of Neutrophils in Lower Limb Peripheral Artery Disease: State of the Art and Future Perspectives

“…In fact, previous research by our group using a mouse model of PAD showed that running wheel training modulates the phenotype of circulating monocytes towards an anti-inflammatory profile. Moreover, training inhibits inflammation and pro-inflammatory macrophage polarization in the lower limb ischemic muscle [ 235 ]. The positive effects of physical activity on inflammation have also been widely demonstrated in various human populations [ 236 , 237 , 238 ].…”