A New Model of Peripheral Arterial Disease: Sustained Impairment of Nutritive Microcirculation and Its Recovery by Chronic Electrical Stimulation

Brown, Margaret D.; Kelsall, Christopher J.; Milkiewicz, Małgorzata; Anderson, Stephen; Hudlická, O

doi:10.1080/10739680590934817

Cited by 22 publications

(27 citation statements)

References 42 publications

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“…Other studies (34,56) have shown that perfusion subsequent to femoral artery occlusion is not correlated with capillarity. Studies have shown that chronic reductions in flow and pressure can result in enhanced constriction and inward remodeling characterized by wall thinning (1,6,8,17,19,41,49,50,64,67), characteristics that occur in human critical limb ischemia (17)(18)(19). Thus, the profound decrease in distal microvascular flow and pressure could result in similar decompensatory events in the precapillary arterioles and small arteries that control the majority of microvascular resistance (3,27,42,77).…”

Section: Discussionmentioning

confidence: 99%

Suppressed hindlimb perfusion in Rac2^−/− and Nox2^−/− mice does not result from impaired collateral growth

Distasi

Case

Ziegler

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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arteriogenesis; hindlimb ischemia; necrosis; regeneration; NADPH oxidase 2 IN THE PERIPHERAL CIRCULATION, the dilation and enlargement of preexisting vessels that form collateral pathways subsequent to arterial occlusion are the primary vascular compensations that preserve tissue viability and maintain function. These vessels dilate within seconds (25,39,45,70) and undergo expansion for weeks (20,25,45,69). In various species, the preexisting vessels are the size of the smallest arteries, and they enlarge ϳ100% (14,20,35,45,56). Available clinical studies have indicated that subsequent to arterial occlusion in the peripheral circulation, the primary vessels that enlarge as collaterals are preexisting arteries (4,29,57). The largest of the preexisting vessels are typically those that become the dominant collaterals (35,45,51). Combined anatomic and modeling studies have predicted that hindlimb flow subsequent to femoral artery occlusion is primarily determined by these collaterals (22,56). This is consistent with studies of segmental resistances that demonstrated that compensation in the collateral vessels is of significantly greater hemodynamic importance than adaptations in the distal microvasculature (43,71,75). Nevertheless, few studies investigating the mechanisms of vascular compensation subsequent to arterial occlusion in mice have specifically identified and studied these preexisting vessels that form the primary collateral pathways. Such investigations are needed because angiogenesis and collateral growth are initiated by different stimuli, and differences exist in the molecules and mechanisms that mediate these important processes (7, 11).Leukocytes, especially lymphocytes (63, 74) and macrophages (2,33,37), have been shown to have an important role in vascular compensation to hindlimb ischemia. Recent studies by Tojo et al. (66) and Urao et al. (72) have established that NADPH oxidase 2 (Nox2)-derived ROS from bone marrowderived cells (BMDCs) have an important role in neovascularization in the ischemic mouse hindlimb. The initial report (66) concluded from microsphere data that collateral growth was impaired, but did not specifically identify collateral bypass vessels or measure their diameters.To investigate the hypothesis that Nox2-derived NAD(P)H oxidase mediates primary collateral growth subsequent to arterial occlusion, the present study used Rac2-null (Rac2 Ϫ/Ϫ ) and Nox2-null (Nox2 Ϫ/Ϫ ) mice and a novel method of identifying primary hindlimb collaterals. Rac2 is expressed primarily, if not exclusively, in hematopoietic cells (38, 52) and binds to and activates Nox2-containing NAD(P)H oxidase (24,40). In addition, leukocytes from Rac2 Ϫ/Ϫ and Nox2 Ϫ/Ϫ mice have impaired function related to reduced ROS production (47,66,72). We present a method to identify the dominant or primary collateral that should be the major collateral supplying flow to

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Section: Discussionmentioning

confidence: 99%

Suppressed hindlimb perfusion in Rac2^−/− and Nox2^−/− mice does not result from impaired collateral growth

Distasi

Case

Ziegler

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…1). 3,9,14,20,27,30,[38][39][40]42,59,62 This threedimensional model is used in calculations of blood flow and oxygen distributions. However, due to the complexity of the system and the number of the parameters that are of physiological interest, we choose a twodimensional cross section of the tissue (400 · 208 lm 3 , boxed in Fig.…”

Section: Anatomymentioning

confidence: 99%

“…51 In addition, average capillary blood velocity is higher in rats that have undergone exercise training. 3 Thus, using empirical relationships for viscosity and hematocrit distribution, 25,46 and experimental measurements of blood oxygenation and velocity in ligated rat EDL 3,16,17,44,46 we simulated blood flow for perfused tissue and partially perfused tissue (where only half of the tissue arterioles have blood flow).…”

Section: Blood Flowmentioning

confidence: 99%

“…33,34 The most common animal model of PAD is surgical ligation of the femoral or iliac arteries. 3,29,44,47,51,53 Although this does not completely reproduce the symptoms of PAD, it has become a valuable tool and a useful correlation. Thus, the simulations we present here are for rat EDL muscle following femoral ligation.…”

Section: Introductionmentioning

confidence: 99%

“…8,18 At rest, the recovery in tissue oxygen content is sufficient, but limb activity is hindered as exercise exerts demands on the provision of oxygen to the tissue. 3,17,44 Our models of VEGF transport in EDL muscle have been applied to resting muscle, 31 exercising muscle, 32 and a femoral ligation model of PAD in resting and exercising muscle. 24 Here, we apply the model to the prediction of VEGF concentration and VEGF gradient formation following three post-ligation therapeutic interventions in EDL muscle: VEGF gene therapy, using an adenoassociated virus (AAV)-type construct; VEGF cellbased therapy, using VEGF-overexpressing myoblasts that incorporate into muscle tissue following injection; and chronic exercise, which increases VEGF receptor expression, and therefore increases the signaling potential of VEGF.…”

Section: Introductionmentioning

confidence: 99%

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Multi-scale Computational Models of Pro-angiogenic Treatments in Peripheral Arterial Disease

Gabhann

Popel

2007

Ann Biomed Eng

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Exercise Training and Peripheral Arterial Disease

Haas

Lloyd

Yang

et al. 2012

Comprehensive Physiology

121

108

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Peripheral arterial disease (PAD) is a common vascular disease that reduces blood flow capacity to the legs of patients. PAD leads to exercise intolerance that can progress in severity to greatly limit mobility, and in advanced cases leads to frank ischemia with pain at rest. It is estimated that 12–15 million people in the United States are diagnosed with PAD, with a much larger population that is undiagnosed. The presence of PAD predicts a 50–1500% increase in morbidity and mortality, depending on severity. Treatment of patients with PAD is limited to modification of cardiovascular disease risk factors, pharmacological intervention, surgery, and exercise therapy. Extended exercise programs that involve walking ~5 times/wk, at a significant intensity that requires frequent rest periods, are most significant. Pre-clinical studies and virtually all clinical trials demonstrate the benefits of exercise therapy, including: improved walking tolerance, modified inflammatory/hemostatic markers, enhanced vasoresponsiveness, adaptations within the limb (angiogenesis, arteriogenesis, mitochondrial synthesis) that enhance oxygen delivery and metabolic responses, potentially delayed progression of the disease, enhanced quality of life indices, and extended longevity. A synthesis is provided as to how these adaptations can develop in the context of our current state of knowledge and events known to be orchestrated by exercise. The benefits are so compelling that exercise prescription should be an essential option presented to patients with PAD in the absence of contraindications. Obviously, selecting for a life style pattern, that includes enhanced physical activity prior to the advance of PAD limitations, is the most desirable and beneficial.

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A New Model of Peripheral Arterial Disease: Sustained Impairment of Nutritive Microcirculation and Its Recovery by Chronic Electrical Stimulation

Cited by 22 publications

References 42 publications

Suppressed hindlimb perfusion in Rac2^−/− and Nox2^−/− mice does not result from impaired collateral growth

Suppressed hindlimb perfusion in Rac2^−/− and Nox2^−/− mice does not result from impaired collateral growth

Multi-scale Computational Models of Pro-angiogenic Treatments in Peripheral Arterial Disease

Exercise Training and Peripheral Arterial Disease

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A New Model of Peripheral Arterial Disease: Sustained Impairment of Nutritive Microcirculation and Its Recovery by Chronic Electrical Stimulation

Cited by 22 publications

References 42 publications

Suppressed hindlimb perfusion in Rac2−/− and Nox2−/− mice does not result from impaired collateral growth

Suppressed hindlimb perfusion in Rac2−/− and Nox2−/− mice does not result from impaired collateral growth

Multi-scale Computational Models of Pro-angiogenic Treatments in Peripheral Arterial Disease

Exercise Training and Peripheral Arterial Disease

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Product

Resources

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Suppressed hindlimb perfusion in Rac2^−/− and Nox2^−/− mice does not result from impaired collateral growth

Suppressed hindlimb perfusion in Rac2^−/− and Nox2^−/− mice does not result from impaired collateral growth