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Skeletal muscle capillarization is a determining factor in gas and metabolite exchange, while its impairments may contribute to the development of sarcopenia. Studies on the potential of resistance training (RT) to induce angiogenesis in older muscles have been inconclusive, and effects of sequential endurance training (ET) and RT on capillarization are unknown. Healthy older men (66.5 ± 3.8 years) were engaged in either 12 weeks of habitual course observation (HC) followed by 12 weeks of RT ( n  = 8), or 12 weeks of high-intensity interval training (HIIT) followed by 12 weeks of RT ( n  = 9). At baseline, following 12 and 24 weeks, m. vastus lateralis biopsies were obtained. (Immuno-)histochemistry was used to assess indices of muscle fiber capillarization, muscle fiber morphology and succinate dehydrogenase (SDH) activity. Single periods of RT and HIIT resulted in similar improvements in capillarization and SDH activity. During RT following HIIT, improved capillarization and SDH activity, as well as muscle fiber morphology remained unchanged. The applied RT and HIIT protocols were thus similarly effective in enhancing capillarization and oxidative enzyme activity and RT effectively preserved HIIT-induced adaptations of these parameters. Hence, both, RT and HIIT, are valid training modalities for older men to improve skeletal muscle vascularization.

Strength Training Increases Insulin-Mediated Glucose Uptake, GLUT4 Content, and Insulin Signaling in Skeletal Muscle in Patients With Type 2 Diabetes Mads K. Holten 1 2 , Morten Zacho 2 , Michael Gaster 3 , Carsten Juel 2 4 , Jørgen F.P. Wojtaszewski 2 5 and Flemming Dela 1 2 1 Department of Medical Physiology, the Panum Institute, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark 2 Copenhagen Muscle Research Centre, Rigshospitalet, Copenhagen, Denmark 3 Departments of Endocrinology and of Pathology, Odense University Hospital, Odense, Denmark 4 August Krogh Institute, Copenhagen, Denmark 5 Institute of Exercise and Sport Sciences, Faculty of Natural Sciences, University of Copenhagen, Copenhagen, Denmark Address correspondence and reprint requests to Flemming Dela, MD, Department of Medical Physiology, the Panum Institute, University of Copenhagen, Blegdamsvej 3, DK 2200 Copenhagen N, Denmark. E-mail: f.dela{at}mfi.ku.dk Abstract Strength training represents an alternative to endurance training for patients with type 2 diabetes. Little is known about the effect on insulin action and key proteins in skeletal muscle, and the necessary volume of strength training is unknown. A total of 10 type 2 diabetic subjects and 7 healthy men (control subjects) strength-trained one leg three times per week for 6 weeks while the other leg remained untrained. Each session lasted no more than 30 min. After strength training, muscle biopsies were obtained, and an isoglycemic-hyperinsulinemic clamp combined with arterio-femoral venous catheterization of both legs was carried out. In general, qualitatively similar responses were obtained in both groups. During the clamp, leg blood flow was higher ( P < 0.05) in trained versus untrained legs, but despite this, arterio-venous extraction glucose did not decrease in trained legs. Thus, leg glucose clearance was increased in trained legs ( P < 0.05) and more than explained by increases in muscle mass. Strength training increased protein content of GLUT4, insulin receptor, protein kinase B-α/β, glycogen synthase (GS), and GS total activity. In conclusion, we found that strength training for 30 min three times per week increases insulin action in skeletal muscle in both groups. The adaptation is attributable to local contraction-mediated mechanisms involving key proteins in the insulin signaling cascade. CS, citrate synthase FFA, free fatty acid G6P, glucose-6-phosphate GS, glycogen synthase HAD, hydroxyacyl-3-dehydrogenase HRP, horseradish peroxidase IRS-1, insulin receptor substrate-1 LDH, lactate dehydrogenase PI, phosphatidylinositol PKB, protein kinase B PMSF, phenylmethylsulfonyl fluoride PVDF, polyvinylidiene diflouride RM, repetition maximum Footnotes Accepted October 17, 2003. Received July 7, 2003. DIABETES

Background Burn injury is associated with a long-standing inflammatory reaction. The use of albumin solutions for plasma volume support is controversial because of concerns of increased capillary leakage, which could aggravate the commonly seen interstitial oedema. Methods In the present open controlled clinical trial, an intravenous infusion of 20% albumin at 3 mL/kg was given over 30 min to 15 burn patients and 15 healthy volunteers. Blood samples and urine were collected for 5 h. Plasma dilution, plasma albumin and colloid osmotic pressure were compared. Mass balance calculations were used to estimate plasma volume expansion and capillary leakage of fluid and albumin. Results The patients were studied between 4 and 14 (median, 7) days after the burn injury, which spread over 7–48% (median, 15%) of the total body surface area. The albumin solution expanded the plasma volume by almost 15%, equivalent to twice the infused volume, in both groups. The urinary excretion exceeded the infused volume by a factor of 2.5. Capillary leakage of albumin occurred at a rate of 3.4 ± 1.5 g/h in burn patients and 3.7 ± 1.6 g/h in the volunteers ( P  = 0.61), which corresponded to 2.4 ± 1.0% and 2.5 ± 1.2% per hour of the intravascular pool ( P  = 0.85). The median half-life of the plasma volume expansion was 5.9 (25th–75th percentiles 2.7–11.7) h in the burn patients and 6.9 (3.4–8.5) h in the volunteers ( P  = 0.56). Conclusions Albumin 20% was an effective volume expander in patients at 1 week post-burn. No relevant differences were found between burn patients and healthy volunteers. Trial registration EudraCT 2016-000996-26 on May 31, 2016.

Background/AimBlood flow deficiencies of the retinal and retrobulbar circulations have been previously reported in open-angle glaucoma (OAG) and other eye diseases. Herein we investigated the effects of image brightness and contrast dynamic altering stimuli (DAS) when viewing a video content on ocular blood flow, intraocular pressure (IOP) and ocular perfusion pressure (OPP) in OAG and healthy subjects.MethodsThirty-five subjects, 25 with OAG (mild to moderate) and 10 healthy controls, were evaluated for blood pressure, IOP, OPP and retinal capillary blood flow before, immediately after, 30 min after and 60 min after using ReviView (a dichoptic video goggles device), which stimulates one eye with a DAS video image that is brighter and with greater contrast than the fellow eye (duration of exposure 30 min). Differences between each subject’s eyes and between OAG and healthy subjects were evaluated using repeated-measures analysis of variance with p<0.05 considered statistically significant.ResultsAll subjects demonstrated a significant increase in OPP in both eyes immediately following viewing. In all DAS eyes, retinal capillary blood flow rose immediately after stimulation and remained elevated for an hour postviewing. Viewing DAS increased retinal blood flow compared with control eyes (p=0.0014, 0.0135 superiorly and p=0.0094, 0.0001 inferiorly, at 30 and 60 min, respectively). OAG eyes had a significant reduction in the number of dormant retinal capillaries (p=0.0174), while healthy eyes demonstrated a larger increase in retinal capillary blood flow (p=0.0006 and p=0.0093 at 60 min, superior and inferior, respectively) following DAS viewing.ConclusionViewing DAS video for 30 min using ReviView increased retina blood flow both in healthy subjects and in patients with OAG.Trial registration number NCT02959593.

The dynamics of fluid vesicles and red blood cells (RBCs) in cylindrical capillary flow is studied by using a three-dimensional mesoscopic simulation approach. As flow velocity increases, a model RBC is found to transit from a nonaxisymmetric discocyteto an axisymmetric parachute shape (coaxial with the flow axis), while a fluid vesicle is found to transit from a discocyte to a prolate ellipsoid. Both shape transitions reduce the flow resistance. The critical velocities of the shape transitions are linearly dependent on the bending rigidity and on the shear modulus of the membrane. Slipper-like shapes of the RBC model are observed around the transition velocities. Our results are in good agreement with experiments on RBCs.

Peripheral myopathy consists of a hallmark of heart failure (HF). Exercise enhanced skeletal muscle angiogenesis, and thus, it can be further beneficial towards the HF-induced myopathy. However, there is limited evidence regarding the exercise type that elicits optimum angiogenic responses of skeletal muscle in HF patients. This study aimed to (a) compare the effects of a high-intensity-interval-training (HIIT) or combined HIIT with strength training (COM) exercise protocol on the expression of angiogenesis-related factors in skeletal muscle of HF patients, and (b) examine the potential associations between the expression of those genes and capillarization in the trained muscles. Thirteen male patients with chronic HF (age: 51 ± 13 y; BMI: 27 ± 4 kg/m2) were randomly assigned to a 3-month exercise program that consisted of either HIIT (N = 6) or COM training (N = 7). Vastus lateralis muscle biopsies were performed pre- and post-training. RT-PCR was used to quantify the fold changes in mRNA expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR-2), hypoxia-inducible factor 1 alpha (HIF-1α), angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2), angiopoietin receptor (Tie2), and matrix metallopeptidase 9 (MMP-9), and immunohistochemistry to assess capillarization in skeletal muscle post-training. There was an overall increase in the expression levels of VEGF, VEGFR-2, HIF-1α, Ang2, and MMP9 post-training, while these changes were not different among groups. Changes in capillary-to-fibre ratio were found to be strongly associated with Tie2 and HIF-1α expression. This was the first study demonstrating that both HIIT and combined HIIT with strength training enhanced similarly the expression profile of angiogenic factors in skeletal muscle of HF patients, possibly driving the angiogenic program in the trained muscles, although those gene expression increases were found to be only partially related with muscle capillarization.

Blood vessels have long been considered as passive conduits for blood and circulating cells that, at best, respond to exogenous cytokines. However, recent work has shown that blood vessels serve as a highly dynamic interface between the circulation and tissues. Augustin et al. review molecular mechanisms of vascular development and function in different organs. Differentiated endothelial cells develop as a sort of cobblestone monolayer to form one of the largest surfaces within the body. Vascular control of the tissue microenvironment is vital, not only for normal tissue development and homeostasis, but also for disease states ranging from inflammation to cancer. Science , this issue p. eaal2379 Blood vessels form one of the body’s largest surfaces, serving as a critical interface between the circulation and the different organ environments. They thereby exert gatekeeper functions on tissue homeostasis and adaptation to pathologic challenge. Vascular control of the tissue microenvironment is indispensable in development, hemostasis, inflammation, and metabolism, as well as in cancer and metastasis. This multitude of vascular functions is mediated by organ-specifically differentiated endothelial cells (ECs), whose cellular and molecular heterogeneity has long been recognized. Yet distinct organotypic functional attributes and the molecular mechanisms controlling EC differentiation and vascular bed–specific functions have only become known in recent years. Considering the involvement of vascular dysfunction in numerous chronic and life-threatening diseases, a better molecular understanding of organotypic vasculatures may pave the way toward novel angiotargeted treatments to cure hitherto intractable diseases. This Review summarizes recent progress in the understanding of organotypic vascular differentiation and function.

Functional neuroimaging, such as fMRI, is based on coupling neuronal activity and accompanying changes in cerebral blood flow (CBF) and metabolism. However, the relationship between CBF and events at the level of the penetrating arterioles and capillaries is not well established. Recent findings suggest an active role of capillaries in CBF control, and pericytes on capillaries may be major regulators of CBF and initiators of functional imaging signals. Here, using two-photon microscopy of brains in living mice, we demonstrate that stimulation-evoked increases in synaptic activity in the mouse somatosensory cortex evokes capillary dilation starting mostly at the first- or second-order capillary, propagating upstream and downstream at 5–20 μm/s. Therefore, our data support an active role of pericytes in cerebrovascular control. The gliotransmitter ATP applied to first- and second-order capillaries by micropipette puffing induced dilation, followed by constriction, which also propagated at 5–20 μm/s. ATP-induced capillary constriction was blocked by purinergic P2 receptors. Thus, conducted vascular responses in capillaries may be a previously unidentified modulator of cerebrovascular function and functional neuroimaging signals.

The majority of the brain’s vasculature is composed of intricate capillary networks lined by capillary pericytes. However, it remains unclear whether capillary pericytes influence blood flow. Using two-photon microscopy to observe and manipulate brain capillary pericytes in vivo, we find that their optogenetic stimulation decreases lumen diameter and blood flow, but with slower kinetics than similar stimulation of mural cells on upstream pial and precapillary arterioles. This slow vasoconstriction was inhibited by the clinically used vasodilator fasudil, a Rho-kinase inhibitor that blocks contractile machinery. Capillary pericytes were also slower to constrict back to baseline following hypercapnia-induced dilation, and slower to dilate towards baseline following optogenetically induced vasoconstriction. Optical ablation of single capillary pericytes led to sustained local dilation and a doubling of blood cell flux selectively in capillaries lacking pericyte contact. These data indicate that capillary pericytes contribute to basal blood flow resistance and slow modulation of blood flow throughout the brain. Vast networks of capillaries feed the brain. Hartmann et al. show that pericyte contractility is critical for maintenance of enduring capillary tone, which sets an optimized rate and distribution of blood flow through brain capillary networks.

The essential function of the circulatory system is to continuously and efficiently supply the O2 and nutrients necessary to meet the metabolic demands of every cell in the body, a function in which vast capillary networks play a key role. Capillary networks serve an additional important function in the central nervous system: acting as a sensory network, they detect neuronal activity in the form of elevated extracellular K⁺ and initiate a retrograde, propagating, hyperpolarizing signal that dilates upstream arterioles to rapidly increase local blood flow. Yet, little is known about how blood entering this network is distributed on a branch-to-branch basis to reach specific neurons in need. Here, we demonstrate that capillary-enwrapping projections of junctional, contractile pericytes within a postarteriole transitional region differentially constrict to structurally and dynamically determine the morphology of capillary junctions and thereby regulate branch-specific blood flow. We further found that these contractile pericytes are capable of receiving propagating K⁺-induced hyperpolarizing signals propagating through the capillary network and dynamically channeling red blood cells toward the initiating signal. By controlling blood flow at junctions, contractile pericytes within a functionally distinct postarteriole transitional region maintain the efficiency and effectiveness of the capillary network, enabling optimal perfusion of the brain.