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Regulation of fiber size, oxidative potential, and capillarization in human muscle by resistance exercise.

To examine the hypothesis that increases in fiber cross-sectional area mediated by high-resistance training (HRT) would result in a decrease in fiber capillarization and oxidative potential, regardless of fiber type, we studied six untrained males (maximum oxygen consumption, 45.6 +/- 2.3 ml. kg-1. min-1; mean +/- SE) participating in a 12-wk program designed to produce a progressive hypertrophy of the quadriceps muscle. The training sessions, which were conducted 3 times/wk, consisted of three sets of three exercises, each performed for 6-8 repetitions maximum (RM). Measurements of fiber-type distribution obtained from tissue extracted from the vastus lateralis at 0, 4, 7, and 12 wk indicated reductions (P < 0.05) in type IIB fibers (15.1 +/- 2.1% vs. 7.2 +/- 1.3%) by 4 wk in the absence of changes in the other fiber types (types I, IIA, and IIAB). Training culminated in a 17% increase (P < 0.05) in cross-sectional area by 12 wk with initial increases observed at 4 wk. The increase was independent of fiber type-specific changes. The number of capillaries in contact with each fiber type increased by 12 wk, whereas capillary contacts-to-fiber area ratios remained unchanged. In a defined cross-sectional field, HRT also increased the capillaries per fiber at 12 wk. Training failed to alter cellular oxidative potential, as measured by succinic dehydrogenase (SDH) activity, regardless of fiber type and training duration. It is concluded that modest hypertrophy induced by HRT does not compromise cellular tissue capillarization and oxidative potential regardless of fiber type.

Adult↗

Myocardial capillarity and maximal capillary diffusion capacity in exercise-trained dogs.

Our purpose was to determine whether changes in myocardial capillarity underlie the exercise training-induced increases in coronary transport capacity previously observed in dogs (J. Appl. Physiol. 58: 468-476, 1985). The approach was to measure capillary diffusion capacity (PS) in working hearts and then measure capillary numerical density (CD), capillary surface area density (CSA), and capillary volume density (CV) in specimens from perfused-fixed hearts. Eight dogs (20-30 kg) were exercise trained (ET) for 12-18 wk and compared with a group of seven control dogs. PS for 51Cr-labeled ethylenediaminetetraacetic acid was determined during maximal adenosine coronary vasodilation with perfusion pressures equal to 100 mmHg in both groups. The trained dogs' maximal PS averaged 58 +/- 10 ml.min-1.100 g-1, which was significantly greater than the control value (31 +/- 6). Maximal PS was linearly related to CV (r = 0.61) and CSA (r = 0.78) in the ET group. However, there was no difference between control and trained average left ventricular CD, CSA, CV, or intercapillary distance. The data indicate that although coronary blood flow capacity and capillary transport capacity may be improved in exercise-trained dog hearts, these changes are not the result of an increase in myocardial capillarity. Rather, the increased maximal PS appears to be due to changes in the determinants of capillary blood flow and/or the relationship between capillary area available for exchange and capillary perfusion.

Animals↗

Skeletal muscle capillarity and angiogenic mRNA levels after exercise training in normoxia and chronic hypoxia.

Gene expression of vascular endothelial growth factor (VEGF), and to a lesser extent of transforming growth factor-beta(1) (TGF-beta(1)) and basic fibroblast growth factor (bFGF), has been found to increase in rat skeletal muscle after a single exercise bout. In addition, acute hypoxia augments the VEGF mRNA response to exercise, which suggests that, if VEGF is important in muscle angiogenesis, hypoxic training might produce greater capillary growth than normoxic training. Therefore, we examined the effects of exercise training (treadmill running at the same absolute intensity) in normoxia and hypoxia (inspired O(2) fraction = 0.12) on rat skeletal muscle capillarity and on resting and postexercise gene expression of VEGF, its major receptors (flt-1 and flk-1), TGF-beta(1), and bFGF. Normoxic training did not alter basal or exercise-induced VEGF mRNA levels but produced a modest twofold increase in bFGF mRNA (P < 0.05). Rats trained in hypoxia exhibited an attenuated VEGF mRNA response to exercise (1.8-fold compared 3.4-fold with normoxic training; P < 0.05), absent TGF-beta(1) and flt-1 mRNA responses to exercise, and an approximately threefold (P < 0.05) decrease in bFGF mRNA levels. flk-1 mRNA levels were not significantly altered by either normoxic or hypoxic training. An increase in skeletal muscle capillarity was observed only in hypoxically trained rats. These data show that, whereas training in hypoxia potentiates the adaptive angiogenic response of skeletal muscle to a given absolute intensity of exercise, this was not evident in the gene expression of VEGF or its receptors when assessed at the end of training.

Animals↗

Fiber capillarization relative to mitochondrial volume in diaphragm of shrew.

The objective was to examine fiber capillarization in relation to fiber mitochondrial volume in the highly aerobic diaphragm of the shrew, the smallest mammal. The diaphragms of four common shrews [Sorex araneus; body mass, 8.2 +/- 1.3 (SE) g] and four lesser shrews (Sorex minutus, 2.6 +/- 0.1 g) were perfusion fixed in situ, processed for electron microscopy, and analyzed by morphometry. Capillary length per fiber volume was extremely high, at values of 8,008 +/- 1,054 and 12,332 +/- 625 mm(-2) in S. araneus and S. minutus, respectively (P = 0.012), with no difference in capillary geometry between the two species. Fiber mitochondrial volume density was 28.5 +/- 2.3% (S. araneus) and 36.5 +/- 1.4% (S. minutus; P = 0.025), yielding capillary length per milliliter mitochondria values (S. araneus, 27.8 +/- 1.5 km; S. minutus, 33.9 +/- 2.2 km; P = 0.06) as high as in the flight muscle of the hummingbird and small bats. The size of the capillary-fiber interface (i.e., capillary surface per fiber surface ratio) per fiber mitochondrial volume in shrew diaphragm was also as high as in bird and bat flight muscles, and it was about two times greater than in rat hindlimb muscle. Thus, whereas fiber capillary and mitochondrial volume densities decreased with increased body mass in S. araneus compared with S. minutus Soricinae shrews, fiber capillarization per milliliter mitochondria in both species was much higher than previously reported for shrew diaphragm, and it matched that of the intensely aerobic flight muscles of birds and mammals.

Aerobiosis↗

Capillarity, fibre types and fibre morphometry in different sampling sites across and along the tibialis anterior muscle of the rat.

Capillarity, fibre types, fibre cross-sectional areas and perimeters were studied along and across the rat tibialis anterior muscle. The muscle was sectioned at three different levels (proximal, equatorial and distal) choosing five sampling fields for measurements at each level (from anterior to posterior and lateral to medial zones). Significant differences were found in the percentage of fibre types and capillarity between different fields of the same muscle section. Slow oxidative fibres were confined to the posterior muscle zone with a maximum of 3.7%. The posterior fields also had a greater percentage of fast oxidative glycolytic fibres at proximal (72.3%) and equatorial (61.3%) levels, but a lower value at the distal level (44.8%) and lower capillary density counts in total cross-section means (758 vs. 1,069 capillaries/mm(2) in equatorial and 1,035 capillaries/mm(2) at proximal levels). The uneven distribution of both fast fibre types and the different degrees of capillarisation along the muscle are statistically significant and may be due to different biomechanical performances along the rat tibialis anterior. Fibre size was significantly larger at the distal level, but no morphometric differences were found across the section of the same level. At the distal level, the mean total fibre area of fast glycolytic fibres (5,130 microm(2)) and fast oxidative glycolytic fibres (2,493 microm(2)) contrasted with values at the proximal (fast glycolytic: 4,070 microm(2), fast oxidative glycolytic: 1,970 microm(2)) and equatorial (fast glycolytic: 3,535 microm(2), fast oxidative glycolytic: 1,714 microm(2)) levels. The differences along and across the muscle show the need to design a standardised procedure for sample location when performing comparative studies of morphofunctional adaptive changes in skeletal muscle. A significant difference between individuals (animals) in all parameters was evident and should be taken into consideration when analysing the variability: the factor 'animal' should be considered in multiway ANOVAs, especially when low sample sizes are used.

Analysis of Variance↗

Sinusoidal capillarization of human hepatocellular carcinoma: possible promotion by fibroblast growth factor.

Expression of acidic and basic fibroblast growth factors (aFGF and bFGF) and von Willebrand factor (vWF) was immunohistochemically investigated in 55 nodules of human hepatocellular carcinoma (HCC), 15 nodules of adenomatous hyperplasia (AH) of the liver and 10 cirrhotic livers (LC). AH, a putative preneoplastic lesion in the cirrhotic liver, was subdivided into ordinary and atypical types: the former was characterized by little cellular and structural atypia and the latter had some atypia equivocal as to benignity and malignancy. The positive rates of FGF (aFGF and/or bFGF) were as follows: 0% in LC, 20% in AH (ordinary and atypical) and 42% in HCC, whereas the positivity of vWF was 10% in LC, 20% in ordinary AH, 30% in atypical AH and 40% in HCC. There was no correlation between the expression of FGF or vWF and the size of HCC. No correlation was also found between the positivity of FGF and that of vWF in HCC and atypical AH. While vWF was not constantly expressed in the vicinity of FGF-positive HCC cells, capillarized sinusoids were significantly more numerous in FGF-positive cases than in FGF-negative cases (p < 0.01). These data indicate that FGF may be pathogenetically linked to the multistep development of HCC in relation to sinusoidal capillarization.

Biomarkers↗

Pulmonary capillaritis. The association with progressive irreversible airflow limitation and hyperinflation.

We report two patients with systemic necrotizing vasculitis (microscopic polyarteritis) and associated recurrent pulmonary capillaritis, in whom progressive irreversible airway dysfunction began approximately 10 yr after disease onset. Their course was characterized by repeated episodes of diffuse alveolar hemorrhage, glomerulonephritis, palpable purpura, and splinter hemorrhages. The lung revealed intraalveolar hemorrhage, neutrophilic infiltration and cellular fragmentation, fibrinoid necrosis of the alveolar interstitium, and parenchymal hemosiderin deposits. No medium-sized vessel involvement, granulomatous inflammation, or bronchiolar obliteration were seen. Renal biopsies revealed focal segmental necrotizing glomerulonephritis, and a cutaneous biopsy in one case showed a leukocytoclastic vasculitis. Immunofluorescent studies of lung and kidney showed minimal or no immunoreactivity. The clinical course and serologic tests did not support another systemic vasculitis, connective tissue disease, or antiglomerular basement membrane antibody disease. The acute episodes responded to antiinflammatory and immunosuppressive therapy. Symptoms, serial pulmonary function tests, and chest imaging documented the development of a progressive irreversible obstructive airway disease. No other predisposing factors were identified. These cases demonstrate the unexpected appearance of an irreversible obstructive airway disease with lung parenchymal hyperinflation after systemic necrotizing vasculitis associated with recurrent pulmonary capillaritis and diffuse alveolar hemorrhage.

Adult↗

Ultrastructural localization of integrin subunits alpha3 and alpha6 in capillarized sinusoids of the human cirrhotic liver.

Normal liver sinusoids are not lined by a basement membrane (BM). In contrast, in the course of development of liver cirrhosis, a structured BM is formed de novo in the space of Disse. This BM contributes to the inhibition of the metabolic function of the liver but the pathogenic background of the formation of this perisinusoidal BM is still unclear. Integrins of the beta1-class are generally essential for BM stability and some of them (such as alpha2beta1, alpha3beta1 and alpha6beta1) appear de novo in the perisinusoidal space of the cirrhotic liver. Their cellular distribution in capillarized sinusoids as well as the correlation between their cellular distribution and the formation of the microvascular BM in the cirrhotic liver has not been shown at the ultrastructural level. In the present work we aimed to clarify this issue. We focused on integrins alpha3beta1 and alpha6beta1 and localised them ultrastructurally in human cirrhotic liver microvessels using postembedding immunogold which allows the ultrastructural localization of antigens with high resolution in the tissue. The newly formed basement membrane of capillarized sinusoids was visualized by means of fixation with addition of tannic acid, which enables the visualization of structures of the extracellular matrix with the highest resolution. Also, we carried out laminin detection using postembedding immunogold. Our results show that both alpha3beta1 and alpha6beta1 are expressed on the surface of both hepatocytes and endothelial cells, i.e. on both sides of the newly formed basement membrane. This latter shows zones of higher density both in close proximity to the endothelial and to the hepatocytic surfaces which resemble laminae densae. We propose that hepatocytes and endothelial cells may, therefore, by expressing such integrins, contribute to the formation of this pathological BM in the microvessels of the human cirrhotic liver. On stellate cells, which are major producers of BM components, both integrins alpha3beta1 and alpha6beta1 were also localized.

Basement Membrane↗

Capillarity in rat skeletal muscle: effects of rapid freezing versus perfusion fixation.

We determined the effects of rapid freezing and perfusion fixation on fiber geometry and capillarity in rat skeletal muscle. Fiber areas were significantly decreased, and capillary densities significantly increased, in perfusion-fixed versus quick-frozen muscle. Significant differences in capillary-to-fiber ratios were not observed, suggesting that differences in fiber geometry, not the methods of quantifying capillaries, accounted for the differences in capillary density. We conclude that estimates of fiber geometry, capillarity, and diffusive gas conductances obtained from perfusion-fixed muscles are subject to significant error due to shrinkage.

Animals↗

Improvement in the capillarity of the left ventricular wall of stroke-prone spontaneously hypertensive rats following angiotensin II receptor blockade.

The effect of the angiotensin II type 1 receptor blockade, candesartan cilexetil (TCV116), on the capillarity of the innermost region of the left ventricular subendocardium were studied in stroke-prone spontaneously hypertensive rats (SHRSP). The rats were fed for 32 days on chow that contained TCV116, the average dose being 0.96 mg/kg/day. Compared with values from control SHRSP, the systolic blood pressure, left ventricular weight and cross-sectional area of cardiomyocytes decreased. A significant increase in the total capillary density was coupled with a decrease of capillary domain areas in all capillary portions. The proportion of venular capillary portions, which was low in control SHRSP, increased significantly, suggesting neoangiogenesis of capillaries. The results indicate that AT1-receptor blockade caused regression of the hypertrophied cardiomyocytes and improved capillarity of the left ventricular wall.

Angiotensin Receptor Antagonists↗

Dynamic changes of capillarization and peri-sinusoid fibrosis in alcoholic liver diseases.

AIM: To investigate the dynamic changes of capillarization and peri-sinusoid fibrosis in an alcoholic liver disease model induced by a new method. METHODS: Male SD rats were randomly divided into 6 groups, namely normal, 4 d, 2 w, 4 w, 9 w and 11 w groups. The animals were fed with a mixture of alcohol for designated days and then decollated, and their livers were harvested to examine the pathological changes of hepatocytes, hepatic stellate cells, sinusoidal endothelial cells, sinusoid, peri-sinusoid. The generation of three kinds of extra cellular matrix was also observed. RESULTS: The injury of hepatocytes became severer as modeling going on. Under electronic microscope, fatty vesicles and swollen mitochondria in hepatocytes, activated hepatic stellate cells with fibrils could been seen near or around it. Fenestrae of sinusoidal endothelial cells were decreased or disappeared, sinusoidal basement was formed. Under light microscopy typical peri-sinusoid fibrosis, gridding-like fibrosis, broaden portal areas, hepatocyte's fatty and balloon denaturation, iron sediment, dot necrosis, congregated lymphatic cells and leukocytes were observed. Type I collagen showed an increasing trend as modeling going on, slightly recovered when modeling stopped for 2 weeks. Meanwhile, type IV collagen decreased rapidly when modeling began and recovered after modeling stopped for 2 weeks. Laminin increased as soon as modeling began and did not recover when modeling stopped for 2 weeks. CONCLUSION: The pathological changes of the model were similar to that of human ALD, but mild in degree. It had typical peri-sinusoid fibrosis, however, capillarization seemed to be instable. It may be related with the reduction of type IV collagen in the basement of sinusoid during modeling.

Animals↗

Pulmonary capillaritis and its relationship to development of emphysema in hypocomplementaemic urticarial vasculitis syndrome.

Hypocomplementaemic urticarial vasculitis syndrome (HUVS) is a rare disorder characterised by complement activation and the presence of C1q precipitins together with a syndrome of urticarial vasculitis, angioedema, arthralgia, ocular inflammation, glomerulonephritis and obstructive lung disease. The pathophysiology of the obstructive airways disease is poorly understood. We report a 46 year-old woman with HUVS who developed progressive obstructive airways disease. Lung biopsy early in the course of her disease revealed pulmonary capillaritis. The disease progressed despite treatment with steroids and cyclosporin and the patient eventually underwent successful double lung transplantation. The explanted lung showed the coexistence of a patchy active vasculitis with severe panacinar emphysema. This is the first description of the histopathological process of HUVS in an explanted lung. Through analysis of serial histopathological specimens and clinical data we show the evolution of pulmonary capillaritis to emphysema, and demonstrate that active vasculitis can coexist with emphysema in patients with HUVS and obstructive airways disease. We suggest that there is a role for ongoing immunosuppressive therapy in these patients.

Biopsy↗

Pulmonary capillaritis and glomerulonephritis in an antineutrophil cytoplasmic antibody-positive patient with prior granulomatous aortitis.

A 59-year-old man showed asynchronous development of noninfectious granulomatous aortitis with aneurysm, followed 9 months later by pulmonary capillaritis and glomerulonephritis in association with elevated serum antineutrophil cytoplasmic antibody levels. To our knowledge, the combination of large artery vasculitis and small vessel systemic vasculitis (capillaritis) has not been previously reported. This case may represent a hybrid type of systemic vasculitis combining features of giant cell arteritis and Wegener's granulomatosis.

Antibodies↗

[Capillarization of the myocardium of the yak].

Organometric and histometric characteristics of various parts of the heart have been performed in the yak, a permanent inhabitant at altitudes of 3,000-5,000 m above the sea level. Forty hearts of mature animals have been studied. Morphometric investigations of capillaries in the muscle fibers have been carried out in the atrial walls, in the right and left auriculae. in the ventricles and in the papillary muscles. The data are presented for each cardiac part: they describe diameters, density and volume of the capillary network and muscle fibers. In order to estimate the degree of capillarization of the cardiac muscle tissue, a new parameter is suggested to be used, when analyzing the morphometric data. It characterizes ratio of capillaries volume. According to the criterion given, a significant difference is stated between the degree of capillarization in the myocardium of the right and left ventricles. We suppose that this adequately reflects an increased loading experienced by the right cardiac parts under a long-lasting effect of altitude factors.

Animals↗

Skeletal muscle capillarity during recovery from chronic hypoxic exposure.

Young male Sprague-Dawley rats were randomly assigned to one of three groups (Chronically Hypoxic, N = 15; Age-Control, N = 15; Weight-Control, N = 15) and studied immediately following a 36-day exposure at a simulated altitude of 5846m or after recovery periods of one, three or seven days. Following preincubation at pH 3.8, cross-sections of soleus muscle were stained by the calcium ATPase method and analyzed for six indices of skeletal muscle capillarity: capillary density (CD), fiber density, number of capillaries around each fiber (CAF), Capillary/fiber ratio (C:F), fiber cross-sectional area (FCSA), and fiber diameter. No differences in skeletal muscle capillarity were observed in chronically hypoxic rats at the termination of exposure or during the seven day recovery period. The Chronically Hypoxics differed significantly (p less than or equal to .05) from both control groups in three different measures of physiologic stress, but showed a definite trend toward recovery in the post-exposure period. This recovery was most apparent in body weight comparisons. The Chronically Hypoxics weighed less than the Age-Controls immediately following the exposure period but gained rapidly during the first three days post-exposure. These rapid body weight increases in rats recovering from chronic exposure to hypoxia suggest that age-controls should not be excluded in favor of weight-controls in similar studies.

Age Factors↗

Capillarization and venularization of hepatic sinusoids in porcine serum-induced rat liver fibrosis: a mechanism to maintain liver blood flow.

The processes of capillarization and venularization of sinusoids after porcine serum-induced rat liver fibrosis were studied by light and electron microscopy. Accompanying the development of fibrosis in the walls of central veins, most of the sinusoidal outlets collapsed, resulting in the formation of hepatic limiting plates around central veins. A few remaining sinusoids underwent capillarization (the development of a basal lamina and the defenestration of the sinusoidal endothelial cell), followed by venularization (the transformation into venules of sinusoids, characterized by the enlargement of the diameters with the lumina being lined with several endothelial cells, which lose fenestrae and develop a basal lamina). These newly formed venules served to maintain blood flow from sinusoids into central veins and thus have been designated the "outlet venules." Diameters of these venules could reach about 25 microns. They were classified into two types: (a) the septal outlet venules, which developed inside the septa; and (b) the angular outlet venules, which drained blood directly from the parenchyma into the fibrotic central veins at the angles between two septa. Associated with venularization, perisinusoidal stellate cells (fat-storing cells or Ito cells) differentiated to myofibroblasts.

Animals↗

Pulmonary capillaritis, alveolar hemorrhage, and recurrent microvascular thrombosis in primary antiphospholipid syndrome.

Pulmonary manifestations of the antiphospholipid syndrome (APS) include pulmonary hypertension, pulmonary embolism, and in patients with the catastrophic APS, respiratory insufficiency associated with diffuse pulmonary infiltrates. There are few descriptions of pathological findings associated with these pulmonary complications. We document pulmonary capillaritis, recurrent microvascular thrombosis and alveolar hemorrhage in patients with APS. These patients have a wide spectrum of clinical presentations, ranging from recurrent episodes of fever, minimal hemoptysis, and mild dyspnea, to respiratory insufficiency requiring mechanical ventilation. Pulmonary involvement can occur alone or simultaneously with other manifestations of APS and may range from mild to severe. Pulmonary capillaritis and alveolar hemorrhage are complications of APS, and whether they are causally related to recurrent thromboembolism and pulmonary hypertension remains undetermined.

Adult↗

Experimental study of the reversibility of sinusoidal capillarization.

This study investigated the reversibility of sinusoidal capillarization in fibrotic rat liver induced by thioacetamide (TAA; 200 mg/kg body weight three times a week). Six weeks later, collagen fibers and hepatic lobular disarrangement were observed on light microscopy and basement membrane formation was noted in the space of Disse. Sinusoidal endothelial fenestrations (SEFs) were decreased in size and number (defenestration), and factor VIII-related antigen was observed in the cytoplasm. We also clarified the phenotypic reversibility of the sinusoidal endothelial cells. After 4 months following discontinuation of TAA exposure, the diameters and numbers of SEFs were increased. Six months later, the basement membrane in the space of Disse disappeared (as assessed by electron microscopy) and 12 months later, factor VIII-related antigen also disappeared. These results indicate that phenotypical changes in the sinusoidal endothelial cells and sinusoidal capillarization in hepatic fibrosis may be reversed.

Animals↗