Angiogenesis in Skeletal Muscle Precede Improvements in Peak Oxygen Uptake in Peripheral Artery Disease Patients

Duscha, Brian D.; Robbins, Jennifer L.; Jones, W. Schuyler; Kraus, William E.; Lye, R. John; Sanders, John M.; Allen, Jason D.; Regensteiner, Judith G.; Hiatt, William R.; Annex, Brian H.

doi:10.1161/atvbaha.111.230441

Cited by 97 publications

(72 citation statements)

References 35 publications

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“…The observation that PPO was lower in the IC patients than the controls is consistent with the limited muscular strength and endurance capacities of IC patients previously described (13,35), and the well-established reduction in their tolerance for physical activities such as walking and cycling (2,28). Several studies have investigated the mechanisms of exercise intolerance in IC patients.…”

Section: Discussionsupporting

confidence: 86%

“…They also exhibit a significantly reduced tolerance for physical activities such as walking and cycling (2,13). This reduction in exercise tolerance leads to functional impairments that are similar to those observed in patients with heart failure (31) and contributes to their impaired mobility, reduced quality of life, and elevated risk for the development of cardiovascular complications (17).…”

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confidence: 99%

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Capillary ultrastructure and mitochondrial volume density in skeletal muscle in relation to reduced exercise capacity of patients with intermittent claudication

Baum

Torchetti

Malik

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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(PAD). Impaired limb blood flow is a major casual factor of lower exercise tolerance in PAD but cannot entirely explain it. We hypothesized that IC is associated with structural changes of the capillary-mitochondria interface that could contribute to the reduction of exercise tolerance in IC patients. Capillary and mitochondrial morphometry were performed after light and transmission electron microscopy using vastus lateralis muscle biopsies of 14 IC patients and 10 age-matched controls, and peak power output (PPO) was determined for all participants using an incremental single-leg kneeextension protocol. Capillary density was lower (411 Ϯ 90 mm Ϫ2 vs. 506 Ϯ 95 mm Ϫ2 ; P Յ 0.05) in the biopsies of the IC patients than in those of the controls. The basement membrane (BM) around capillaries was thicker (543 Ϯ 82 nm vs. 423 Ϯ 97 nm; P Յ 0.01) and the volume density of mitochondria was lower (3.51 Ϯ 0.56% vs. 4.60 Ϯ 0.74%; P Յ 0.01) in the IC patients than the controls. In the IC patients, a higher proportion of capillaries appeared with collapsed slit-like lumen and/or swollen endothelium. PPO was lower (18.5 Ϯ 9.9 W vs. 33.5 Ϯ 9.4 W; P Յ 0.01) in the IC patients than the controls. We suggest that several structural alterations in skeletal muscle, either collectively or separately, contribute to the reduction of exercise tolerance in IC patients. capillary; morphometry; peripheral arterial disease; skeletal muscle; transmission electron microscopy PERIPHERAL ARTERIAL DISEASE (PAD) is an atherosclerotic disease characterized by stenosis or occlusion of the conduit arteries of the lower limbs (20,36). Risk factors associated with PAD include advancing age, cigarette smoking, diabetes mellitus, arterial hypertension, and disturbances in lipid metabolism (12). While many PAD patients are asymptomatic, the arterial narrowing leads to ischemia and hypoxia of the supplied tissues and in severe cases, this manifests as critical limb ischemia (CLI), usually requiring surgical interventions. Intermittent claudication (IC), which is typically described as a cramp-like muscle pain during exercise, is the most commonly reported symptom of PAD and is usually the first noted symptom of the disease.Patients with IC have limited muscular strength and endurance capacities (35), reduced cardiorespiratory fitness (V O 2 peak ), and demonstrate reduced oxygen uptake kinetics at the onset of exercise (6). They also exhibit a significantly reduced tolerance for physical activities such as walking and cycling (2, 13). This reduction in exercise tolerance leads to functional impairments that are similar to those observed in patients with heart failure (31) and contributes to their impaired mobility, reduced quality of life, and elevated risk for the development of cardiovascular complications (17).Impaired limb blood flow is commonly assumed to be the main casual factor of the reduction in exercise tolerance in PAD but cannot entirely explain it. For example, restoration of blood flow capacity with percutaneous endovascular revascularizat...

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Section: Discussionsupporting

confidence: 86%

mentioning

confidence: 99%

Capillary ultrastructure and mitochondrial volume density in skeletal muscle in relation to reduced exercise capacity of patients with intermittent claudication

Baum

Torchetti

Malik

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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“…This effect is thought to be mediated in part by an increase in skeletal muscle capillarization, which enhances the surface area for oxygen delivery and nutrient exchange (14). Despite this beneficial adaptation, some reports indicate that repeated ischemic exercise can lead to skeletal muscle damage, as revealed by increased tissue fibrosis (24) and activation of proteolytic signaling cascades (13) following exercise training in patients with IC.…”

Section: Discussionmentioning

confidence: 99%

Effects of oral N-acetylcysteine on walking capacity, leg reactive hyperemia, and inflammatory and angiogenic mediators in patients with intermittent claudication

Silva

Roseguini

Chehuen

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…16 Skeletal muscle biopsy procedures were performed as described previously. 16 miRNA was isolated from skeletal muscle lysates as described above.…”

Section: Methodsmentioning

confidence: 99%

Modulation of miR29a improves impaired post-ischemic angiogenesis in hyperglycemia

Chen

Okeke

Ayalew

et al. 2017

Exp Biol Med (Maywood)

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Individuals with diabetes mellitus suffer from impaired angiogenesis and this contributes to poorer peripheral arterial disease outcomes. In experimental peripheral arterial disease, angiogenesis and perfusion recovery are impaired in mice with diabetes. We recently showed that a disintegrin and metalloproteinase domain-containing protein 12 (ADAM12) is upregulated in ischemic endothelial cells and plays a key role in post-ischemic angiogenesis and perfusion recovery following experimental peripheral arterial disease. Here we investigated the role of miR29a in the regulation of endothelial cell ADAM12 expression in ischemia and how hyperglycemia negatively affects this regulation. We also explored whether modulating miR29a can improve impaired post-ischemic angiogenesis associated with hyperglycemia. Additionally, we tested whether miR29a modulation could improve post ischemic angiogenesis in the setting of impaired vascular endothelial growth factor signaling. We forced miR29a expression in ischemic endothelial cells and assessed ADAM12 expression. We also evaluated whether hyperglycemia in vivo and in vitro impair ischemia-induced ADAM12 upregulation and miR29a downregulation. Lastly, we determined whether modulating endothelial cell miR29a expression in ischemia and hyperglycemia could improve impaired endothelial cell functions. We found under ischemic conditions where ADAM12 is upregulated in endothelial cells, miR29a is downregulated. Forced expression of miR29a in ischemic endothelial cell prevented ADAM12 upregulation . In ischemic hind limbs of mice with type 1 diabetes and in endothelial cells exposed to simulated ischemia plus hyperglycemia, ADAM12 upregulation and miR29a downregulation were blunted while angiogenesis was impaired. Knocking down miR29a with an miR29a inhibitor was sufficient to improve ADAM12 upregulation and angiogenesis in simulated ischemia plus hyperglycemia. It was also sufficient to improve perfusion recovery in type 1 diabetes mellitus mice in vivo and angiogenesis in vitro even when vascular endothelial growth factor signaling was impaired with blocking antibodies. In conclusion, MiR29a regulates endothelial cell ADAM12 upregulation in ischemia and this is impaired in hyperglycemia. Modulating miR29a improves impaired post-ischemic angiogenesis associated with hyperglycemia. Impact statement Individuals with diabetes are more likely to develop peripheral arterial disease (PAD), and when PAD is present, in those with diabetes, it is more severe and there is currently no effective medical treatment for impaired blood flow which occurs in diabetics with PAD. The current work advances the field by providing an understanding of a molecular mechanism involved in impaired post ischemic angiogenesis in diabetes. It shows for the first time that failure to downregulate miR29a in ischemic diabetic tissues is a major contributing factor to poor perfusion recovery in experimental PAD, and miR29a is elevated in skeletal muscle samples from human diabetics compared with levels in those without diabetes. Knocking down the elevated miR29a in ischemic diabetic mouse hind limbs improved perfusion recovery following experimental PAD. This shows miR29a modulation as a novel therapeutic target for improving blood flow in diabetics with PAD.

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Angiogenesis in Skeletal Muscle Precede Improvements in Peak Oxygen Uptake in Peripheral Artery Disease Patients

Cited by 97 publications

References 35 publications

Capillary ultrastructure and mitochondrial volume density in skeletal muscle in relation to reduced exercise capacity of patients with intermittent claudication

Capillary ultrastructure and mitochondrial volume density in skeletal muscle in relation to reduced exercise capacity of patients with intermittent claudication

Effects of oral N-acetylcysteine on walking capacity, leg reactive hyperemia, and inflammatory and angiogenic mediators in patients with intermittent claudication

Modulation of miR29a improves impaired post-ischemic angiogenesis in hyperglycemia

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