Advances and challenges in skeletal muscle angiogenesis.

The role of capillaries is to serve as the interface for delivery of oxygen and removal of metabolites to/from tissues. During the past decade there has been a proliferation of studies that have advanced our understanding of angiogenesis demonstrating tissue capillary supply is under strict control during health, but poorly controlled in disease - resulting in either excessive capillary growth (pathological angiogenesis) or losses in capillarity (rarefaction). Given that skeletal muscle comprises nearly 40% of body mass in humans, skeletal muscle capillary density has a significant impact on metabolism, endocrine function, and locomotion, and is tightly regulated at many different levels. Skeletal muscle is also high adaptable, and thus one of the few organ systems which can be experimentally manipulated (e.g. by exercise) to study physiologic regulation of angiogenesis. This review will focus on 1) the methodological concerns that have arisen in determining skeletal muscle capillarity, and 2) highlight the concepts that are reshaping our understanding of the angio-adaptation process. We also summarize selected new findings (physical influences, molecular changes and ultrastructural rearrangement of capillaries) that identify areas of future research with the greatest potential to expand our understanding of how angiogenesis is normally regulated, and that may also help to better understand conditions of uncontrolled (pathologic) angiogenesis

Non-invasive management of peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) is common and symptoms can be debilitating and lethal. Risk management, exercise, radiological and surgical intervention are all valuable therapies, but morbidity and mortality rates from this disease are increasing. Circulatory enhancement can be achieved using simple medical electronic devices, with claims of minimal adverse side effects. The evidence for these is variable, prompting a review of the available literature. METHODS: Embase and Medline were interrogated for full text articles in humans and written in English. Any external medical devices used in the management of peripheral arterial disease were included if they had objective outcome data. RESULTS: Thirty-one papers met inclusion criteria, but protocols were heterogenous. The medical devices reported were intermittent pneumatic compression (IPC), electronic nerve (NMES) or muscle stimulators (EMS), and galvanic electrical dressings. In patients with intermittent claudication, IPC devices increase popliteal artery velocity (49-70 %) and flow (49-84 %). Gastrocnemius EMS increased superficial femoral artery flow by 140 %. Over 4.5-6 months IPC increased intermittent claudication distance (ICD) (97-150 %) and absolute walking distance (AWD) (84-112 %), with an associated increase in quality of life. NMES of the calf increased ICD and AWD by 82 % and 61-150 % at 4 weeks, and 26 % and 34 % at 8 weeks. In patients with critical limb ischaemia IPC reduced rest pain in 40-100 % and was associated with ulcer healing rates of 26 %. IPC had an early limb salvage rate of 58-83 % at 1-3 months, and 58-94 % at 1.5-3.5 years. No studies have reported the use of EMS or NMES in the management of CLI. CONCLUSION: There is evidence to support the use of IPC in the management of claudication and CLI. There is a building body of literature to support the use of electrical stimulators in PAD, but this is low level to date. Devices may be of special benefit to those with limited exercise capacity, and in non-reconstructable critical limb ischaemia. Galvanic stimulation is not recommended

MRI of Arterial Flow Reserve in Patients with Intermittent Claudication: Feasibility and Initial Experience

Objectives: The aim of this work was to develop a MRI method to determine arterial flow reserve in patients with intermittent claudication and to investigate whether this method can discriminate between patients and healthy control subjects. Methods: Ten consecutive patients with intermittent claudication and 10 healthy control subjects were included. All subjects underwent vector cardiography triggered quantitative 2D cine MR phase-contrast imaging to obtain flow waveforms of the popliteal artery at rest and during reactive hyperemia. Resting flow, maximum hyperemic flow and absolute flow reserve were determined and compared between the two groups by two independent MRI readers. Also, interreader reproducibility of flow measures was reported. Results: Resting flow was lower in patients compared to controls (4.961.6 and 11.163.2 mL/s in patients and controls, respectively (p,0.01)). Maximum hyperemic flow was 7.362.9 and 16.463.2 mL/s (p,0.01) and the absolute flow reserve was 2.461.6 and 5.361.3 mL/s (p,0.01), respectively in patients and controls. The interreader coefficient of variation was below 10 % for all measures in both patients and controls. Conclusions: Quantitative 2D MR cine phase-contrast imaging is a promising method to determine flow reserve measures in patients with peripheral arterial disease and can be helpful to discriminate patients with intermittent claudication fro

Losartan modulates muscular capillary density and reverses thiazide diuretic-exacerbated insulin resistance in fructose-fed rats

The renin–angiotensin system (RAS) is involved in the pathogenesis of insulin sensitivity (IS). The role of RAS in insulin resistance and muscular circulation has yet to be elucidated. Therefore, this study sought to determine the mechanisms of angiotensin II receptor blockers (ARBs) and/or diuretics on IS and capillary density (CD) in fructose-fed rats (FFRs). Sprague-Dawley rats were fed either normal chow (control group) or fructose-rich chow for 8 weeks. For the last 4 weeks, FFRs were allocated to four groups: an FFR group and groups treated with the thiazide diuretic hydrochlorothiazide (HCTZ), with the ARB losartan, or both. IS was evaluated by the euglycemic hyperinsulinemic glucose clamp technique at week 8. In addition, CD in the extensor digitorum longus muscle was evaluated. Blood pressure was significantly higher in the FFRs than in the controls. HCTZ, losartan and their combination significantly lowered blood pressure. IS was significantly lower in the FFR group than in the controls and was even lower in the HCTZ group. Losartan alone or combined with HCTZ significantly increased IS. In all cases, IS was associated with muscular CD, but not with plasma adiponectin or lipids. These results indicate that losartan reverses HCTZ-exacerbated insulin resistance, which can be mediated through the modulation of muscular circulation in rats with impaired glucose metabolism

Thrombospondins in the heart: potential functions in cardiac remodeling

Cardiac remodeling after myocardial injury involves inflammation, angiogenesis, left ventricular hypertrophy and matrix remodeling. Thrombospondins (TSPs) belong to the group of matricellular proteins, which are non-structural extracellular matrix proteins that modulate cell–matrix interactions and cell function in injured tissues or tumors. They interact with different matrix and membrane-bound proteins due to their diverse functional domains. That the expression of TSPs strongly increases during cardiac stress or injury indicates an important role for them during cardiac remodeling. Recently, the protective properties of TSP expression against heart failure have been acknowledged. The current review will focus on the biological role of TSPs in the ischemic and hypertensive heart, and will describe the functional consequences of TSP polymorphisms in cardiac disease

Elongation, proliferation & migration differentiate endothelial cell phenotypes and determine capillary sprouting

<p>Abstract</p> <p>Background</p> <p>Angiogenesis, the growth of capillaries from preexisting blood vessels, has been extensively studied experimentally over the past thirty years. Molecular insights from these studies have lead to therapies for cancer, macular degeneration and ischemia. In parallel, mathematical models of angiogenesis have helped characterize a broader view of capillary network formation and have suggested new directions for experimental pursuit. We developed a computational model that bridges the gap between these two perspectives, and addresses a remaining question in angiogenic sprouting: how do the processes of endothelial cell elongation, migration and proliferation contribute to vessel formation?</p> <p>Results</p> <p>We present a multiscale systems model that closely simulates the mechanisms underlying sprouting at the onset of angiogenesis. Designed by agent-based programming, the model uses logical rules to guide the behavior of individual endothelial cells and segments of cells. The activation, proliferation, and movement of these cells lead to capillary growth in three dimensions. By this means, a novel capillary network emerges out of combinatorially complex interactions of single cells. Rules and parameter ranges are based on literature data on endothelial cell behavior in vitro. The model is designed generally, and will subsequently be applied to represent species-specific, tissue-specific in vitro and in vivo conditions.</p> <p>Initial results predict tip cell activation, stalk cell development and sprout formation as a function of local vascular endothelial growth factor concentrations and the Delta-like 4 Notch ligand, as it might occur in a three-dimensional in vitro setting. Results demonstrate the differential effects of ligand concentrations, cell movement and proliferation on sprouting and directional persistence.</p> <p>Conclusion</p> <p>This systems biology model offers a paradigm closely related to biological phenomena and highlights previously unexplored interactions of cell elongation, migration and proliferation as a function of ligand concentration, giving insight into key cellular mechanisms driving angiogenesis.</p

Impact of inactivity and exercise on the vasculature in humans

The effects of inactivity and exercise training on established and novel cardiovascular risk factors are relatively modest and do not account for the impact of inactivity and exercise on vascular risk. We examine evidence that inactivity and exercise have direct effects on both vasculature function and structure in humans. Physical deconditioning is associated with enhanced vasoconstrictor tone and has profound and rapid effects on arterial remodelling in both large and smaller arteries. Evidence for an effect of deconditioning on vasodilator function is less consistent. Studies of the impact of exercise training suggest that both functional and structural remodelling adaptations occur and that the magnitude and time-course of these changes depends upon training duration and intensity and the vessel beds involved. Inactivity and exercise have direct “vascular deconditioning and conditioning” effects which likely modify cardiovascular risk

Blunted angiogenesis and hypertrophy are associated with increased fatigue resistance and unchanged aerobic capacity in old overloaded mouse muscle.

We hypothesize that the attenuated hypertrophic response in old mouse muscle is (1) partly due to a reduced capillarization and angiogenesis, which is (2) accompanied by a reduced oxidative capacity and fatigue resistance in old control and overloaded muscles, that (3) can be rescued by the antioxidant resveratrol. To investigate this, the hypertrophic response, capillarization, oxidative capacity, and fatigue resistance of m. plantaris were compared in 9- and 25-month-old non-treated and 25-month-old resveratrol-treated mice. Overload increased the local capillary-to-fiber ratio less in old (15 %) than in adult (59 %) muscle (P < 0.05). Although muscles of old mice had a higher succinate dehydrogenase (SDH) activity (P < 0.05) and a slower fiber type profile (P < 0.05), the isometric fatigue resistance was similar in 9- and 25-month-old mice. In both age groups, the fatigue resistance was increased to the same extent after overload (P < 0.01), without a significant change in SDH activity, but an increased capillary density (P < 0.05). Attenuated angiogenesis during overload may contribute to the attenuated hypertrophic response in old age. Neither was rescued by resveratrol supplementation. Changes in fatigue resistance with overload and aging were dissociated from changes in SDH activity, but paralleled those in capillarization. This suggests that capillarization plays a more important role in fatigue resistance than oxidative capacity