Muscle Capillary Density Research Articles

Skeletal Muscle Involvement in Friedreich Ataxia and Potential Effects of Recombinant Human Erythropoietin Administration on Muscle Regeneration and Neovascularization

Friedreich ataxia (FRDA) is caused by reduced expression of the mitochondrial protein frataxin. Cardiac muscle involvement has been attributed to mitochondrial dysfunction, but involvement of skeletal muscle has not been fully investigated. Improved motor skills in FRDA patients after administration of recombinant human erythropoietin (rhuEPO) have been reported. To elucidate the characteristics of skeletal muscle in FRDA and assess the potential effects of rhuEPO on skeletal muscle neovascularization and regeneration, 7 genetically confirmed FRDA patients underwent biopsy of the gastrocnemius muscle before and after administration of 3,000 international units of rhuEPO 3 times per week for 2 months. Muscle tissue was investigated using standard histologic methods, immunohistochemistry, and biochemical assays of mitochondrial enzymes. In pretreatment FRDA samples, there were neurogenic and myopathic changes and reduced capillary density versus that in healthy control biopsies (n = 4). Satellite cells were increased, but markers of satellite cell activation and differentiation did not differ from controls. Respiratory chain complex and citrate synthase activities were reduced in FRDA and remained unchanged after treatment. Administration of rhuEPO resulted in increases in muscle capillary densities and in endothelial progenitor cells in peripheral blood. These data indicate that there are morphological and biochemical abnormalities of skeletal muscle in FRDA. The rhuEPO-induced changes were subtle, but increased capillary density might result in improved oxygen supply and myofiber function.

Toward a mouse model of hind limb ischemia to test therapeutic angiogenesis

Several clinical trials are currently evaluating stem cell therapy for patients with critical limb ischemia that have no other surgical or endovascular options for revascularization. However, these trials are conducted with different protocols, including use of different stem cell populations and different injection protocols, providing little means to compare trials and guide therapy. Accordingly, we developed a murine model of severe ischemia to allow methodic testing of relevant clinical parameters. High femoral artery ligation and total excision of the superficial femoral artery was performed on C57BL/6 mice. Mononuclear cells (MNCs) were isolated from the bone marrow of donor mice, characterized using fluorescence-activated cell sorting, and injected (5×10(5) to 2×10(6)) into the semimembranosus (proximal) or gastrocnemius (distal) muscle. Vascular and functional outcomes were measured using invasive Doppler imaging, laser Doppler perfusion imaging, and the Tarlov and ischemia scores. Histologic analysis included quantification of muscle fiber area and number as well as capillary density. Blood flow and functional outcomes were improved in MNC-treated mice compared with controls over 28 days (flow: P<.0001; Tarlov: P=.0004; ischemia score: P=.0002). MNC-treated mice also showed greater gastrocnemius fiber area (P=.0053) and increased capillary density (P=.0004). Dose-response analysis showed increased angiogenesis and gastrocnemius fiber area but no changes in macroscopic vascular flow or functional scores. Overall functional outcomes in mice injected proximally to the ischemic area were similar to mice injected more distally, but muscle flow, capillary density, and gastrocnemius fiber area were increased (P<.05). High femoral ligation with complete excision of the superficial femoral artery is a reliable model of severe hind limb ischemia in C57BL/6 mice that shows a response to MNC treatment for functional and vascular outcomes. A dose response to the injection of MNCs appears to be present, at least microscopically, suggesting that an optimal cell number for stem cell therapy exists and that preclinical testing needs to be performed to optimally guide human trials. Injection of MNCs proximal to the site of ischemia may provide different outcomes compared with distal injection and warrants additional study.

Systemic adenosine‐induced impairment of endothelial glycocalyx barrier properties is associated with a reduction in functional capillary density in hindlimb skeletal muscle of rats

ObjectiveTo determine the effect of systemic adenosine infusion on dextran accessibility in capillaries of rat skeletal muscle.MethodsA bolus of fluorescently‐labeled small (40 kDa) dextrans (Dex40) and large (2000 kDa) dextrans (Dex2000) was i.v. infused in anesthetized rats. This was done in control rats (N=4) and in rats that received continuous adenosine infusion (2 mg/ml; 1.5 ml/h) (N=3) for 15 minutes. 3 minutes after dextran infusion, calf muscles were removed and sectioned. Images were captured using fluorescence microscopy. For both tracers, the number as well as the diameter of tracer‐filled capillaries was determined.ResultsIn control rats the diameter of Dex2000 filling in capillaries was smaller compared to Dex40, 3.27 ± 0.05 μm versus 3.48 ± 0.08 μm (MEAN ± SEM). During adenosine infusion, diameters for both tracers did not differ anymore, 3.24 ± 0.24 (Dex40) versus 3.34 ± 0.27 μm (Dex2000). The number of dextran perfused capillaries in control animals was smaller for Dex2000 than for Dex40, 357 ± 31 versus 658 ± 51 and decreased more for Dex2000 (270 ± 22, P&lt;0.05) than for Dex40 (572 ± 60, NS) during adenosine infusion.ConclusionGlycocalyx recruitment during systemic adenosine infusion in rats is associated with a decrease in vascular anatomic volume in resting hindlimb muscle.Sponsored by Dutch Heart Foundation (NHS2009B56)

Blocking of myostatin and activins increase muscle protein synthesis and mTORC1 signaling but decreases capillary density

Blocking of myostatin and activins increases muscle mass but the underlying mechanisms are unknown and whether during muscle growth capillary density is maintained. Soluble activin receptor IIb fused to Fc (ActRIIB/Fc) was produced in house inhibiting myostatin, activin A and activin B signaling in a biological assay. Healthy mice were injected with ActRIIB/Fc either 1x or 2x/wk for 2 weeks. The 2x/wk dosage seemed to increase muscle mass slightly more. In gastrocnemius muscle fiber size increased ~15–20 % whereas the capillary density decreased ~20 %. In muscle homogenate, PGC‐1α and cytochrome C protein decreased 40–50 %. To elucidate mechanisms for these, we next sacrificed mice 1 or 2 days after ActRIIB/Fc or PBS injection. Muscle protein synthesis increased in gastrocnemius ~30 % 2 days after ActRIIB/Fc correlating with increased mTORC1 signaling (increased phosphorylation (p) of rpS6, r=0.8, p&lt;0.01). In contrast, muscle protein ubiquitination and p‐FoxO remained unchanged. Both p‐p38 and p‐Erk 1/2 MAPKs decreased 2 days after ActRIIB/Fc. Of novel proteins possibly associated with TGFβ blocking, REDD1 increased 1–2 days after ActRIIB/Fc. Importance of this finding needs to be studied in the future. In conclusion, blocking of ActRIIB pathway increases muscle protein synthesis and mTORC1 signaling but decreases MAPK signaling after 2 days and decreases muscle capillary density.

A chocolate a day keeps the doctor away?

A chocolate a day keeps the doctor away?

Exercise training attenuates the hypermuscular phenotype and restores skeletal muscle function in the myostatin null mouse

Myostatin regulates both muscle mass and muscle metabolism. The myostatin null (MSTN(-/-)) mouse has a hypermuscular phenotype owing to both hypertrophy and hyperplasia of the myofibres. The enlarged muscles display a reliance on glycolysis for energy production; however, enlarged muscles that develop in the absence of myostatin have compromised force-generating capacity. Recent evidence has suggested that endurance exercise training increases the oxidative properties of muscle. Here, we aimed to identify key changes in the muscle phenotype of MSTN(-/-) mice that can be induced by training. To this end, we subjected MSTN(-/-) mice to two different forms of training, namely voluntary wheel running and swimming, and compared the response at the morphological, myocellular and molecular levels. We found that both regimes normalized changes of myostatin deficiency and restored muscle function. We showed that both exercise training regimes increased muscle capillary density and the expression of Ucp3, Cpt1α, Pdk4 and Errγ, key markers for oxidative metabolism. Cross-sectional area of hypertrophic myofibres from MSTN(-/-) mice decreased towards wild-type values in response to exercise and, in this context, Bnip3, a key autophagy-related gene, was upregulated. This reduction in myofibre size caused an increase of the nuclear-to-cytoplasmic ratio towards wild-type values. Importantly, both training regimes increased muscle force in MSTN(-/-) mice. We conclude that impaired skeletal muscle function in myostatin-deficient mice can be improved through endurance exercise-mediated remodelling of muscle fibre size and metabolic profile.

The curious case of anabolic resistance: old wives' tales or new fables?

the progressive loss of muscle mass, commonly termed sarcopenia, accompanies the process of healthy aging ([27][1]). The underlying basis of this condition, in a very simplistic view, would be at a more advanced age skeletal muscle proteins are being lost because of an imbalance between muscle

Association of peak aerobic power with capillary density but not oxidative potential in human vastus lateralis muscle.

In this study, we have postulated that in healthy males, peak aerobic power ([Formula: see text]) would associate with muscle capillary density rather than oxidative potential, regardless of fibre type or subtype. To test this, active but untrained volunteers (n = 11) were separated into high (HI) and low (LO) groups based on [Formula: see text] obtained during a progressive cycle task to fatigue. The 26% higher (P< 0.05) [Formula: see text] observed in HI (40.8± 1.5mL·kg(-1)·min(-1), mean± SE) compared with LO ( 51.4± 0.90mL·kg(-1)·min(-1), mean± SE) was not accompanied by differences in age (21.3± 1.2 compared with 21.1± 0.63years, respectively) or body mass (72.4± 4.6 compared with 71.6± 1.9kg, respectively). Tissue samples obtained from the vastus lateralis indicated greater (P< 0.05) capillary counts per fibre (CC;+24%) in HI compared with LO, regardless of fibre type (I, IIA, IIX, IIAX). Capillary density (CD) as measured in a field of defined area was also elevated (+22%; P< 0.05), as was the number of capillaries per fibre (+22%; P< 0.05). No differences were observed between the 2 groups in the distribution, area, and the CC/fibre area ratio in the different fibre types and subtypes. Similarly, there was no difference between the HI and LO groups in oxidative potential, as measured by succinic dehydrogenase activity in the different fibre types. It is concluded that the higher capillary density may contribute to improved vascular conductance and the elevated [Formula: see text] observed in the untrained participants.

Should Willy Wonka have been a sports nutritionist?

Should Willy Wonka have been a sports nutritionist?

Effect of Pulmonary Rehabilitation on Peripheral Muscle Fiber Remodeling in Patients With COPD in GOLD Stages II to IV

In most patients with COPD, rehabilitative exercise training partially reverses the morphologic and structural abnormalities of peripheral muscle fibers. However, whether the degree of improvement in muscle fiber morphology and typology with exercise training varies depending on disease severity remains unknown. Forty-six clinically stable patients with COPD classified by GOLD (Global Initiative for Obstructive Lung Disease) as stage II (n = 14), III (n = 18), and IV (n = 14) completed a 10-week comprehensive pulmonary rehabilitation program consisting of high-intensity exercise three times weekly. At baseline, muscle fiber mean cross-sectional area and capillary density did not significantly differ between patients with COPD and healthy control subjects, whereas muscle fiber type I and II proportion was respectively lower (P < .001) and higher (P < .002) in patients with GOLD stage IV compared with healthy subjects and patients with GOLD stages II and III. Exercise training improved, to a comparable degree, functional capacity and the St. George Respiratory Questionnaire health-related quality of life score across all three GOLD stages. Vastus lateralis muscle fiber mean cross-sectional area was increased (P < .001) in all patient groups (stage II: from 4,507 ± 280 μm² to 5,091 ± 271 μm² [14% ± 3%]; stage III: from 3,753 ± 258 μm² to 4,212 ± 268 μm² [14% ± 3%]; stage IV: from 3,961 ± 266 μm² to 4,551 ± 262 μm² [17% ± 5%]), whereas all groups exhibited a comparable reduction (P < .001) in type IIb fiber proportion (stage II: by 6% ± 2%; stage III: by 6% ± 1%; stage IV: by 7% ± 1%) and an increase (P < .001) in capillary to fiber ratio (stage II: from 1.48 ± 0.10 to 1.81 ± 0.10 [23% ± 5%]; stage III: from 1.29 ± 0.06 to 1.56 ± 0.09 [21% ± 5%]; stage IV: from 1.43 ± 0.10 to 1.71 ± 0.13 [18 ± 3%]). The magnitude of changes in the aforementioned variables did not differ across GOLD stages. Functional capacity and morphologic and typologic adaptations to rehabilitation in peripheral muscle fibers were similar across GOLD stages II to IV. Pulmonary rehabilitation should be implemented in patients at all COPD stages.

Effects of Two Different Half-Squat Training Programs on Fatigue During Repeated Cycling Sprints in Soccer Players

This study compared the effects of two different half-squat training programs on the repeated-sprint ability of soccer players during the preseason. Twenty male professional soccer players were divided into 2 groups: One group (S-group) performed 4 sets of 5 repetitions with 90% of their 1-repetition maximum (1RM), and the other group (H-group) performed 4 sets of 12 repetitions with 70% of 1RM, 3 times per week for 6 weeks, in addition to their common preseason training program. Repeated-sprint ability was assessed before and after training by 10 × 6-second cycle ergometer sprints separated by 24 seconds of passive recovery. Maximal half-squat strength increased significantly in both groups (p < 0.01), but this increase was significantly greater in the S-group compared with the H-group (17.3 ± 1.9 vs. 11.0 ± 1.9%, p < 0.05). Lean leg volume (LLV) increased only in the H-group. Total work over the 10 sprints improved in both groups after training, but this increase was significantly greater in the second half (8.9 ± 2.6%) compared with the first half of the sprint test (3.2 ± 1.7%) only in the S-group. Mean power output (MPO) expressed per liter of LLV was better maintained during the last 6 sprints posttraining only in the S-group, whereas there was no change in MPO per LLV in the H-group over the 10 sprints. These results suggest that resistance training with high loads is superior to a moderate-load program, because it increases strength without a change in muscle mass and also results in a greater improvement in repeated sprint ability. Therefore, resistance training with high loads may be preferable when the aim is to improve maximal strength and fatigue during sprinting in professional soccer players.

Vascular Gene Transfer of SDF-1 Promotes Endothelial Progenitor Cell Engraftment and Enhances Angiogenesis in Ischemic Muscle

Gene therapy approaches to enhance endothelial progenitor cell (EPC) homing may augment cell engraftment to ischemic tissue and lead to a greater therapeutic response. Therefore, we assessed the effects of ultrasound-mediated (UM) transfection of the chemokine stromal cell-derived factor-1 (SDF-1) on homing and engraftment of intravenously administered EPCs and the subsequent angiogenic response in chronically ischemic skeletal muscle. Bone marrow-derived EPCs were isolated from donor Fisher 344 rats, cultured and labeled in preparation for injection into recipient animals via a jugular vein. Using a model of chronic hindlimb ischemia in rats, we demonstrated that UM destruction of intravenous carrier microbubbles loaded with SDF-1 plasmid DNA resulted in targeted transfection of the vascular endothelium within ischemic muscle and greater local engraftment of EPCs. The combination of SDF-1gene therapy and EPCs lead to the greatest increase in tissue perfusion and microvascular density within ischemic muscle, compared to no treatment or either monotherapy alone. Our results demonstrate that UM transfection of SDF-1 improves EPC targeting to chronically ischemic tissue, enhancing vascular engraftment and leading to a more robust neovascularization response.

Relationship between leg muscle capillary density and peak hyperemic blood flow with endurance capacity in peripheral artery disease

The aim of this study was to determine if skeletal muscle capillary density is lower in patients with peripheral artery disease (PAD) and if capillary density relates to functional limitations. PAD patients with intermittent claudication (IC) have a decreased exercise tolerance due to exercise-induced muscle ischemia. Despite the apparent role diminished arterial flow has in this population, the degree of walking pain and functional limitation is not entirely explained by altered hemodynamics of the affected limbs. We hypothesized that skeletal muscle capillary density is lower in PAD and is related to the functional impairment observed in this population. Sixty-four patients with PAD and 56 controls underwent cardiopulmonary exercise testing and a gastrocnemius muscle biopsy. A subset of these patients (48 PAD and 47 controls) underwent peak hyperemic flow testing via plethysmography. Capillary density in PAD patients was lower compared with controls (P < 0.001). After adjustment for several baseline demographic imbalances the model relating capillary density to peak oxygen consumption (Vo(2)) remained significant (P < 0.001). In PAD subjects, capillary density correlated with peak Vo(2), peak walking time (PWT), and claudication onset time (COT). Peak hyperemic blood flow related to peak Vo(2) in both PAD and control subjects. PAD is associated with lower capillary density, and capillary density is related to the functional impairment as defined by a reduced peak Vo(2), PWT, and COT. These findings suggest that alterations in microcirculation may contribute to functional impairment capacity in PAD.

Progressive Hyperglycemia across the Glucose Tolerance Continuum in Older Obese Adults Is Related to Skeletal Muscle Capillarization and Nitric Oxide Bioavailability

Reduced tissue nutrient exposure may aid in the progression of glucose intolerance. The aim of the study was to examine peripheral tissue glucose disposal in relation to muscle capillarization and plasma nitric oxide bioavailability. Participants were carefully matched for age, adiposity, and lipid status and stratified into normal (n = 20), impaired (n = 20), and type 2 diabetic (n = 20) glucose-tolerant groups. The study was conducted in an outpatient setting at a Clinical Research Unit. Older, obese men and women (n = 60; age, 65 ± 1 yr; body mass index, 32.7 ± 0.5 kg/m(2)) participated in the study. We performed a cross-sectional study. Body composition, energy metabolism, aerobic fitness (maximum oxygen consumption), insulin sensitivity (glucose clamp), vastus lateralis muscle morphology, and plasma nitric oxide were assessed. Although subjects were identical with respect to age, body composition, energy expenditure, and lipid status, insulin-stimulated glucose disposal and maximum oxygen consumption showed progressive decline with increasing glucose intolerance. Muscle fiber type composition and mitochondrial density were not different between groups. However, capillary density markedly declined with advancing glucose intolerance (1.86 ± 0.31, 1.70 ± 0.28, 1.42 ± 0.24 capillary/fiber; P < 0.05), a trend that was mirrored by fasting plasma nitric oxide concentrations (26.3 ± 3.6, 19.8 ± 2.3, 15.2 ± 2.1 μmol/liter; P < 0.05). Furthermore, skeletal muscle capillary density correlated with insulin sensitivity (r = 0.65; P < 0.001). Impaired muscle capillarization and reduced nutrient exposure to the metabolizing tissue may play a major role in the progression of insulin resistance across the glucose tolerance continuum, independent of age, adiposity, lipid status, and resting energy metabolism. These data also highlight plasma nitric oxide as a potential surrogate marker of these impairments and may be indicative of the progression toward type 2 diabetes.

Influence of intermittent administration of parathyroid hormone on muscle tissue and bone healing in orchiectomized rats or controls

Influence of human parathyroid hormone (hPTH 1-34) on muscle and bone healing was studied in either orchiectomized (Orx at 8 months of age) or sham-operated male rats. Eleven-month-old Sprague-Dawley rats underwent bilateral transverse metaphyseal osteotomy of tibia and were divided into four groups (n=12): 1) sham-vehicle, 2) sham group-PTH everyday, 3) Orx-vehicle, 4) Orx-PTH everyday, and 5) Orx-PTH every other day. PTH dosage was 40 μg/kg body weight. After 5 weeks, fiber cross-sectional area, capillary density, and enzyme activity (lactate dehydrogenase, citrate synthase, and complex I) were measured in soleus (MS), gastrocnemius (MG), and longissimus (ML) muscles; tibiae were analyzed by computed tomographical, histological, and gene expression analyses. The effect of PTH in all rats was increased serum osteocalcin, cortical and callus densities and callus area. In sham rats capillary density was increased in limb muscles (MS: 1.3-1.7, MG: 1.2-1.4 capillaries/fiber), and rate of osseous bridging of osteotomy was enhanced (67-100%). In Orx rats serum creatine kinase was decreased (6670-2847 U/l), and bone genes (Igf-1, osteoprotegerin, and receptor activator of nuclear factor kB ligand) were up-regulated. Cross-sectional area, enzyme activity, food intake, weight of body, visceral organs, adipose tissue, MG, and MS were not affected by PTH. PTH had a favorable effect on muscle capillary density and improved bone healing being more effective in sham rats and having no adverse systemic effect. The effect was less if PTH was applied every other day. The findings may show up trends for therapeutic treatment of male patients.

325 Iugr Affects Long Term Postischemic Neovascularization Capacity

Introduction: Cardiovascular disease is a major cause of premature death. The severity of such diseases has been suggested to result from insufficient angiogenesis processes. Low birth weight is now recognized as a risk factor of mortality for such disease. However, the vascular repair capacity after ischemia in IUGR adult offspring is unknown. Objective: To show how postischemic neovascularization capacity is affected in 12 mo-old adult IUGR rat offspring (maternal gestational low protein diet). Material and Methods: The unilateral hind limb ischemia model by femoral artery resection was used to study the neovascular capacity; the controlateral hind limb served as a reference for each animal. Laser Doppler imaging was used to assess blood flow perfusion in both hind limb after ischemia. Capillary densities of the anterior tibial muscle from both controlateral and ischemic limbs was measured at day 21. Results: After ischemia, IUGR offspring showed marked decreased blood flow in ischemic hind limb from day 1 (-60 % vs -40 % in IUGR and control offspring, p < 0.05). At day 21, while ischemia promoted neovascularization in control offspring (+ 22 %), vascular density was decreased in IUGR ischemic hind limb by 30 % (p < 0.05). Moreover, muscle capillary density of non-ischemic hind limb was higher in IUGR as compared with control offspring (+ 20 %, p < 0.05). Conclusion: Postischemic neovascularization capacity following hind limb ischemia is affected in IUGR adult rat offspring. Angiogenic repair pathways, more than basal capillary density, may be affected in such condition.

High-intensity interval training improves microvascular and macrovascular function and insulin sensitivity

Both micro and macrovascular adaptations contribute to the mechanisms by which reduced physical activity increases the risk for cardiovascular disease and insulin resistance. In a parallel abstract,1 the authors report...

Impaired Oxygen Utilization in Skeletal Muscle of CRPS I Patients

The purpose of this study was to evaluate oxygen extraction and utilization in end stage chronic complex regional pain syndrome type I (CRPS I) patients undergoing amputation and to relate these to muscle histology of the amputated limb. In 25 patients with severe CRPS I requiring amputation of the affected limb venous blood samples and in 11 patients skeletal muscle specimens were analyzed. The mean venous oxygen saturation (S(v)O(2)) value (94.3% ± 4.0%) of the affected limb was significantly higher than S(v)O(2) values found in healthy subjects (77.5% ± 9.8%) pointing to a severely decreased oxygen diffusion or utilization within the affected limb. Histologic analysis showed a significant decrease of type I fibers and a significant increase of type IIB fibers. Ultrastructural investigations of soleus skeletal muscle capillaries revealed thickened endothelial cells and thickened basement membranes. Muscle capillary densities were decreased in comparison with literature data. High venous oxygen saturation levels were partially explained by impaired diffusion of oxygen due to thickened basement membrane and decreased capillary density. This study shows that venous oxygen saturation is significantly increased in chronic end stage CRPS I patients corresponding with impaired oxygen diffusion. The abnormal skeletal muscle findings points to severe disuse but only partially explain the impaired diffusion of oxygen; mitochondrial dysfunction seems a likely explanation in addition.

Regulation of skeletal muscle regeneration by CCR2-activating chemokines is directly related to macrophage recruitment.

Muscle regeneration requires CC chemokine receptor 2 (CCR2) expression on bone marrow-derived cells; macrophages are a prominent CCR2-expressing cell in this process. CCR2-/- mice have severe impairments in angiogenesis, macrophage recruitment, and skeletal muscle regeneration following cardiotoxin (CTX)-induced injury. However, multiple chemokines activate CCR2, including monocyte chemotactic proteins (MCP)-1, -3, and -5. We hypothesized that MCP-1 is the chemokine ligand that mediates the impairments present in CCR2-/- mice. We examined muscle regeneration, capillary density, and cellular recruitment in MCP-1-/- and CCR2-/- mice following injury. Muscle regeneration and adipocyte accumulation, but not capillary density, were significantly impaired in MCP-1-/- compared with wild-type (WT) mice; however, muscle regeneration and adipocyte accumulation impairments were not as severe as observed in CCR2-/- mice. Although tissue levels of MCP-5 were elevated in MCP-1-/- mice compared with WT, the administration of MCP-5 neutralizing antibody did not alter muscle regeneration in MCP-1-/- mice. While neutrophil accumulation after injury was similar in all three mouse strains, macrophage recruitment was highest in WT mice, intermediate in MCP-1-/- mice, and severely impaired in CCR2-/- mice. In conclusion, while the absence of MCP-1 resulted in impaired macrophage recruitment and muscle regeneration, MCP-1-/- mice exhibit an intermediate phenotype compared with CCR2-/- mice. Intermediate macrophage recruitment in MCP-1-/- mice was associated with similar capillary density to WT, suggesting that fewer macrophages may be needed to restore angiogenesis vs. muscle regeneration. Finally, other chemokines, in addition to MCP-1 and MCP-5, may activate CCR2-dependent regenerative processes resulting in an intermediate phenotype in MCP-1-/- mice.

Exercise Training in Patients With Advanced Chronic Heart Failure (NYHA IIIb) Promotes Restoration of Peripheral Vasomotor Function, Induction of Endogenous Regeneration, and Improvement of Left Ventricular Function

Attenuated peripheral perfusion in patients with advanced chronic heart failure (CHF) is partially the result of endothelial dysfunction. This has been causally linked to an impaired endogenous regenerative capacity of circulating progenitor cells (CPC). The aim of this study was to elucidate whether exercise training (ET) affects exercise intolerance and left ventricular (LV) performance in patients with advanced CHF (New York Heart Association class IIIb) and whether this is associated with correction of peripheral vasomotion and induction of endogenous regeneration. Thirty-seven patients with CHF (LV ejection fraction 24+/-2%) were randomly assigned to 12 weeks of ET or sedentary lifestyle (control). At the beginning of the study and after 12 weeks, maximal oxygen consumption (Vo(2)max) and LV ejection fraction were determined; the number of CD34(+)/KDR(+) CPCs was quantified by flow cytometry and CPC functional capacity was determined by migration assay. Flow-mediated dilation was assessed by ultrasound. Capillary density was measured in skeletal muscle tissue samples. In advanced CHF, ET improved Vo(2)max by +2.7+/-2.2 versus -0.8+/-3.1 mL/min/kg in control (P=0.009) and LV ejection fraction by +9.4+/-6.1 versus -0.8+/-5.2% in control (P<0.001). Flow-mediated dilation improved by +7.43+/-2.28 versus +0.09+/-2.18% in control (P<0.001). ET increased the number of CPC by +83+/-60 versus -6+/-109 cells/mL in control (P=0.014) and their migratory capacity by +224+/-263 versus -12+/-159 CPC/1000 plated CPC in control (P=0.03). Skeletal muscle capillary density increased by +0.22+/-0.10 versus -0.02+/-0.16 capillaries per fiber in control (P<0.001). Twelve weeks of ET in patients with advanced CHF is associated with augmented regenerative capacity of CPCs, enhanced flow-mediated dilation suggestive of improvement in endothelial function, skeletal muscle neovascularization, and improved LV function. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique Identifier: NCT00176384.