Increased angiogenic response but deficient arteriolization and abnormal microvessel ultrastructure in critical leg ischaemia

Ho, TK; Rajkumar, Vineeth; Black, Carol M.; Abraham, David; Baker, DM

doi:10.1002/bjs.5496

Cited by 31 publications

(35 citation statements)

References 28 publications

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“…A meta-analysis of 33 trials (38) reported the mean effect of exercise therapy on the ankle to brachial blood pressure index (ABI) to be trivial (0.03 Ϯ 0.06). Thus factors other than blood flow, e.g., the skeletal muscle structure, likely contribute the reduction in exercise tolerance in PAD patients and the improvement seen with exercise therapy.Pericapillary basement membrane thickening (7,8,24) and alterations of the volume density (V v ) of mitochondria (V v mito ) (1, 15) are examples of ultrastructural changes in skeletal muscle in patients with CLI, the late, most severe stages of PAD. However, skeletal muscle samples from CLI patients are heterogeneous and contain large deposits of fat and connective tissue, and there is a higher proportion of degenerated fibers compared with that observed in patients with IC (11), which limits their potential to be used in quantitative investigations.…”

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confidence: 99%

“…Pericapillary basement membrane thickening (7,8,24) and alterations of the volume density (V v ) of mitochondria (V v mito ) (1, 15) are examples of ultrastructural changes in skeletal muscle in patients with CLI, the late, most severe stages of PAD. However, skeletal muscle samples from CLI patients are heterogeneous and contain large deposits of fat and connective tissue, and there is a higher proportion of degenerated fibers compared with that observed in patients with IC (11), which limits their potential to be used in quantitative investigations.…”

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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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confidence: 99%

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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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“…Blood vessels in the MCL of ACL-t knees do not lack smooth muscle. [2]. Our focus has centered on the pathologic changes that occur in the MCL following rupture of the anterior cruciate ligament.…”

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“…Following anterior cruciate ligament (ACL) rupture, hypertrophy of the medial collateral ligament (MCL), capsule and synovium occur [2], preceding meniscal tears, cartilage lesions, and sub-chondral sclerosis ultimately leading to osteoarthritis [2]. Our focus has centered on the pathologic changes that occur in the MCL following rupture of the anterior cruciate ligament.…”

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Vascular structure and function in the medial collateral ligament of anterior cruciate ligament transected rabbit knees

et al. 2014

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To determine if decreased vascular responsiveness in the medial collateral ligament (MCL) of anterior cruciate ligament transected (ACL-t) rabbit knees is due to pericyte deficiency associated with angiogenesis. Vascular responses to potassium chloride (KCl), phenylephrine, acetylcholine, and sodium nitroprusside (SNP) were evaluated in ACL-t rabbit knees (n ¼ 6) and control knees (n ¼ 5) using laser speckle perfusion imaging. Ligament degeneration was determined by ultrasound imaging. Vascular and pericyte volume were measured using quantitative immunohistochemical volumetric analysis using CD31 and a-smooth muscle actin antibodies with co-localization analysis. Perfusion was increased in the ACL-t rabbits 2.5-fold. Responsiveness to phenylephrine, SNP, and acetylcholine was significantly decreased in the ACL knee while no change in KCl responses was seen. MCL ultrasound imaging revealed decreased collagen organization, increased ligament thickness, and increased water content in the ACL-t MCL. Vascular Volume was increased fourfold in ACL deficient knees, while pericyte volume to endothelial volume was not changed. No difference in CD31 and a-SMA co-localization was found. Blood vessels in the MCL of ACL-t knees do not lack smooth muscle. [2]. Our focus has centered on the pathologic changes that occur in the MCL following rupture of the anterior cruciate ligament. Our hope is that understanding early secondary OA pathology future interventions may be developed to preserve joint function and improve outcomes.The rabbit ACL transected (ACL-t) model has been extensively tested and is well known model of secondary OA having a reliable and reproducible natural history [3]. Joint instability induces osteoarthritic degeneration of rabbit knees, whereas immediate ACL reconstruction prevents joint degeneration [7]. The MCL tensile strength decreases after ACL-t, exacerbating joint instability [7]. A strong angiogenic response occurs in the MCL following ACL-t [8].The MCL vasculature does not respond appropriately to vasoactive mediators such as phenylephrine (PHE) and acetylcholine (ACH) after ACL-t [9,10].These processes are known as endothelial dysfunctionloss of vasodilatory responses mediated through the endothelium; and vascular dysfunction-loss of vasocontractile responses mediated through smooth muscle. Typically endothelial and vascular dysfunction are associated with inflammation [11]. Alternatively, angiogenesis may lead to decreased vascular smooth muscle and therefore decreased dilatory and contractile responses as has been found in synovium of rheumatoid arthritis patients [12].Quantification of the a-smooth muscle actin (a-SMA) content can be utilized to determine the anatomic state of blood vessels and if these vessels are capable of vasoregulation. 1 A volume based ratiometric analysis of the endothelial volume (CD31 label) to a-SMA content has been previously utilized to determine the composition of angiogenic vessels, 2,3 and using similar methods will define the vascular anatomy of the MC...

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“…This is followed by the degradation of the basement membrane, reorganization of original vessel walls and controlled proteolysis of the matrix molecules [20][21][22][23]. Angiopoietin-1 (Ang-1) is of particular interest because receptors for angiopoetin are located in endothelial cells [16,17].…”

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confidence: 99%

The Formation of Blood Vessel After the Administration of the Plasmid Encoding Ang-1 Gene in Fischer Rats

et al. 2016

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Approximately 1% of patients with peripheral artery disease develop critical lower limb ischemia (CLI) with an unfavorable prognosis. Within one year after the diagnosis, more than 30% of patients with lower limb CLI require amputation [1][2][3][4].The development of endovascular treatment using angioplasty and stents have decreased the amputation rate among patients with CLI. HowCardiovascular disease is the leading cause of death in the Western world and the World Health Organization estimates that over 17 million people worldwide die of cardiovascular disorders each year [1]. There are more than 25 million people in Europe and the United States who have chronic ischemia affecting lower limbs caused by atherosclerotic lesions in the peripheral arteries. A -research concept and design; B -collection and/or assembly of data; C -data analysis and interpretation; D -writing the article; E -critical revision of the article; F -final approval of article AbstractBackground. Chronic limb ischemia is a serious clinical problem. Patients who do not qualify for standard treatment may benefit from novel gene therapies. Objectives. This study evaluated angiogenesis following intramuscular injections of angiogenic plasmid Ang-1 in Fisher rats. Material and Methods. Twenty rats had plasmids injected intramuscularly in their hind limbs. The study group consisted of 10 animals which received the Ang-1 plasmid, while the control group consisted of 10 rats that received an empty plasmid. All the animals were euthanized after 12 weeks and tissue samples from the hind limb thigh muscles and internal organs were harvested for histological and immunohistochemical examinations. To assess the angiogenesis the number of vessels in the hind limb muscles visualized by the SMA and FVIII markers was counted for each animal in five separate microscopic fields. Results. There were no pathological lesions or any signs of neoplastic angiogenesis in any of the 20 rats. The number of vessels visualized by the FVIII marker in the study group was two times higher than in the control group (median: 12, range: 7-25 vs. median: 6, range: 2-15; p < 0.0001). The median estimated that the number of vessels visualized by the SMA marker is 63% higher in the study group compared to the control group (median: 6.5, range: 1-12 vs. median: 4, range: 0-10; p = 0.0008). Conclusions. Intramuscular injections of Ang-1 plasmids induced angiogenesis in the rat hind limb muscles (Adv Clin Exp Med 2016, 25, 4, 611-615).

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Increased angiogenic response but deficient arteriolization and abnormal microvessel ultrastructure in critical leg ischaemia

Abstract: A physiological angiogenic response was found in CLI, but the microvessels had an abnormal ultrastructure. A lack of active cell proliferation suggests that the angiogenic response may have been exhausted.

Cited by 31 publications

References 28 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

Vascular structure and function in the medial collateral ligament of anterior cruciate ligament transected rabbit knees

The Formation of Blood Vessel After the Administration of the Plasmid Encoding Ang-1 Gene in Fischer Rats

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