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Walking exercise is the most effective noninvasive therapy that improves walking ability in peripheral artery disease (PAD). Biologic mechanisms by which exercise improves walking in PAD are unclear. This review summarizes evidence regarding effects of walking exercise on lower extremity skeletal muscle in PAD. In older people without PAD, aerobic exercise improves mitochondrial activity, muscle mass, capillary density, and insulin sensitivity in skeletal muscle. However, walking exercise increases lower extremity ischemia in people with PAD, and therefore, mechanisms by which this exercise improves walking may differ between people with and without PAD. Compared with people without PAD, gastrocnemius muscle in people with PAD has greater mitochondrial impairment, increased reactive oxygen species, and increased fibrosis. In multiple small trials, walking exercise therapy did not consistently improve mitochondrial activity in people with PAD. In one 12-week randomized trial of people with PAD randomized to supervised exercise or control, supervised treadmill exercise increased treadmill walking time from 9.3 to 15.1 minutes, but simultaneously increased the proportion of angular muscle fibers, consistent with muscle denervation (from 7.6% to 15.6%), while angular myofibers did not change in the control group (from 9.1% to 9.1%). These findings suggest an adaptive response to exercise in PAD that includes denervation and reinnervation, an adaptive process observed in skeletal muscle of people without PAD during aging. Small studies have not shown significant effects of exercise on increased capillary density in lower extremity skeletal muscle of participants with PAD, and there are no data showing that exercise improves microcirculatory delivery of oxygen and nutrients in patients with PAD. However, the effects of supervised exercise on increased plasma nitrite abundance after a treadmill walking test in people with PAD may be associated with improved lower extremity skeletal muscle perfusion and may contribute to improved walking performance in response to exercise in people with PAD. Randomized trials with serial, comprehensive measures of muscle biology, and physiology are needed to clarify mechanisms by which walking exercise interventions improve mobility in PAD.

Purpose: To evaluate the vascular characteristics of the choriocapillaris in eyes with pachychoroid as compared with normal controls., Methods: Eyes with pachychoroid disease were defined as those with a history of central serous chorioretinopathy or peripapillary pachychoroid syndrome. Pachychoroid without disease was defined as eyes with no history of disease with a subfoveal choroidal thickness ≥ the age-adjusted 95th percentile thickness. Frame-averaged optical coherence tomography angiography images of the choriocapillaris obtained with a Zeiss Plex Elite were binarized, skeletonized, and evaluated for vascular branching parameters., Results: There were 7 normal control subjects, 10 subjects with pachychoroid without disease, and 17 pachychoroid disease subjects. Mean choriocapillaris vessel segment length was 12.19 µm in eyes with pachychoroid disease as compared with 11.48 µm in normal controls and 11.62 µm in pachychoroid without disease (P = 0.003 and P = 0.006, respectively). The branches per square millimeter were fewer in pachychoroid disease (1,215), as compared with normal controls (1,471) or pachychoroid without disease (1,384; P < 0.001, and P = 0.002, respectively). The choriocapillaris vessel diameter was larger, but the fractal dimension was smaller in pachychoroid disease eyes as compared with normal eyes or pachychoroid without disease eyes. There was no statistically significant difference between normal controls and pachychoroid without disease for any measured vascular parameter of the choriocapillaris., Conclusion: Choriocapillaris vascular parameters suggest that pachychoroid is not necessarily pathologic. It is possible that choroidal thickening is an epiphenomenon, and there are more significant vascular parameters that are related to disease. These concepts may help guide future prospective studies.

Background: Autologous fat grafting is an efficient procedure in plastic surgery. However, its long-term tissue absorption is variable and technique-dependent. Platelet-rich plasma positively affects fat-grafting outcomes but still has shortcomings, and platelet-rich fibrin has been reported to have efficacy in fat transplantation. Here, we compared the effects of platelet-rich fibrin and platelet-rich plasma in fat grafting using histologic analysis., Methods: Twenty rabbits were divided randomly into two groups. In each group, the groin region fat pads were cut into 1-mm granules. Platelet-rich fibrin-treated or platelet-rich plasma-treated fat granules were transplanted into one ear, whereas the contralateral ear was transplanted with normal saline-treated fat granules. Histologic characteristics and capillary density of grafted tissue were analyzed 12 weeks after fat grafting., Results: The grafted fat in the platelet-rich fibrin-treated group showed higher tissue retention than that in the control group [weight retention, 19.57 percent (interquartile range, 13.87 to 29.93 percent) versus 9.04 percent (interquartile range, 6.16 to 16.80 percent), p < 0.05; and volume retention, 18.00 percent (interquartile range, 10.50 to 26.50 percent) versus 8.00 percent (interquartile range, 5.75 to 13.25 percent), p < 0.05] and higher neovascularized capillary density than that in the platelet-rich plasma-treated and control groups. The platelet-rich plasma-treated group showed higher vessel density without superior tissue retention compared with the control group., Conclusion: Platelet-rich fibrin increased tissue retention, quality, and vascularization of grafted fat compared with the control group and showed effects similar to those of platelet-rich plasma on tissue retention and histologic graft improvement.

Purpose: To describe the macular deep capillary plexus (DCP) in normal eyes using optical coherence tomography angiography., Methods: Retrospective study including 41 consecutive normal eyes imaged using optical coherence tomography angiography (RTVue XR Avanti; Optovue Inc). Default autosegmentation of the superficial capillary plexus (SCP) and DCP, and manual adjustments of "deep settings" were used to analyze the organization of the normal macular microvascularization and to investigate in vivo the connection between these capillary networks., Results: Mean age was 31 years (range, 22-55 years). The SCP and DCP had 2 different organizations, but the plexus autosegmentation was imperfect: In 68% of cases, the image of the SCP variably superimposed on the DCP, interfering with its analysis. The SCP was composed on average of 7 pairs of arterioles and venules obvious on each 3-mm × 3-mm optical coherence tomography angiography scanning area. The DCP was composed of a capillary vortex arrangement, whose centers were aligned along the course of the macular superficial venules., Conclusion: The SCP and DCP had two different topographic organizations. The pattern of the capillary units converging into capillary vortexes highly suggests that they drain into the superficial venules. The different structural properties of the SCP and DCP could explain the differences in flow resistance and perfusion.

Hypertension is a common side effect in cancer patients treated with inhibitors of vascular endothelial growth factor/vascular endothelial growth factor receptor-2 signaling and may represent a marker of clinical benefit. Functional rarefaction (a decrease in perfused microvessels) or structural rarefaction (a reduction in anatomic capillary density) may play an important role in the development of hypertension. We investigated whether sunitinib caused impairment of microvascular function and/or reduction of capillary density in patients with metastatic renal cell cancer (mRCC). Sixteen mRCC patients were treated with sunitinib (50 mg/day). Assessments of 24-h ambulatory blood pressure, microvascular endothelial function by laser Doppler fluxmetry, and capillary density by capillary microscopy were performed at baseline and days 14 and 28. Median blood pressure had increased on day 14 (systolic 10 mmHg, P<0.01 and diastolic blood pressure 8 mmHg, P<0.01). Capillary density had decreased from 69 to 61 capillaries/mm (P<0.01). This decrease was related to the increase in systolic and diastolic blood pressure (r=-0.57, P<0.05 and r=-0.68, P<0.01, respectively). A more pronounced decrease in capillary density was associated with increased visibility of the subpapillary plexus (P=0.041). Preliminary findings indicated that median progression-free survival was significantly prolonged in patients with a greater than 6 capillaries/mm decrease in density as compared with patients with a less pronounced decrease (P=0.044). In conclusion, reduction in skin capillary density is associated with a rise in blood pressure during sunitinib therapy and, by itself, might be useful as a predictive marker of clinical outcome.

Background and Purpose: Animal models developed in rats and mice have become indispensable in preclinical cerebrovascular research. Points of interest include the investigation of the vascular bed and the morphology and function of the arterial, capillary, and venous vessels. Because of their extremely small caliber, in vivo examination of these vessels is extremely difficult. In the present study we have developed a method to provide fast 3D in vivo analysis of cerebral murine vessels using volume computed tomography-angiography (vCTA)., Methods: Using an industrial X-ray inspection system equipped with a multifocus cone beam X-ray source and a 12-bit direct digital flatbed detector, high-speed vCTA (180 degrees rotation in 40 s. at 30 fps) was performed in anesthetized mice. During the scan an iodinated contrast agent was infused via a tail vein. Images were reconstructed using a filtered backprojection algorithm. Image analysis was performed by maximum intensity projection (MIP) and 3D volume reconstruction., Results: All mice tolerated i.v. injection of the iodinated contrast agent well. Smallest achievable voxel size of raw data while scanning the whole neurocranium was 16 mum. Anatomy of cerebral vessels was assessable in all animals, and anatomic differences between mouse strains could easily be detected. Mean vessel diameter was measured in C57BL/6 and BALBc mice. Changes of vessel caliber were assessable by repeated vCTA., Conclusions: Ultra fast in vivo vCTA of murine cerebral vasculature is feasible at resolutions down to 16 mum. The technique allows the assessment of vessel caliber changes in living mice, thus providing an interesting tool to monitor different features such as vasospasm or vessel patency.

Purpose of Review: Plasma expanders are reviewed to determine their ability to restore microvascular function as a means for extending the transfusion trigger and delaying the use of blood transfusions. This outcome is currently achievable because of the emergence of a new understanding of optimal tissue function that prioritizes maintenance of functional capillary density, which results from the normalization of blood viscosity via the increase in plasma viscosity with new viscogenic colloids., Recent Findings: Use of viscous plasma expanders in experimental models of extreme hemodilution, hemorrhagic shock and endotoxemia shows that the limiting factor in anemia is not oxygen-carrying capacity but the decline of microvascular function due to the lowering of functional capillary density. In support of this hypothesis, we find that viscogenic colloids including high-molecular-weight starches, dextrans, polyvinylpyrrolidone, keratin and polyethylene glycol-conjugated albumin maintain or restore microvascular function in extreme hemodilution, polyethylene glycol-conjugated albumin yielding the best results., Summary: Preclinical studies show that polyethylene glycol-conjugated albumin at concentrations in the range of 2-4% extends the transfusion trigger, providing the more extended and complete microvascular and systemic recovery from hemorrhagic shock, extreme hemodilution and endotoxemia, postponing the need of reestablish intrinsic blood oxygen-carrying capacity to hemoglobin concentrations lower than those associated with accepted transfusion triggers.

It has been shown that right ventricle (RV) hypertrophy involves significant compensatory vascular growth and remodeling. The objective of the present study was to determine the functional implications of the vascular growth and remodeling through a full flow analysis of arterial tree down to first capillary segments. A computer reconstruction of RV branches including the proximal right coronary artery to the posterior descending artery was established based on measured morphometric data in arrested, vasodilated porcine heart. The flows were computed throughout the reconstructed trees based on conservation of mass and momentum and appropriate pressure boundary conditions. It was found that the flow rate was significantly increased in large epicardial coronary arteries in hypertrophic as compared with control hearts but normalized in the intramyocardial coronary arteries and smaller vessels in RV hypertrophy primarily because of the significant increase in number of arterioles. Furthermore, the wall shear stress was restored to nearly homeostatic levels throughout most of the vasculature after 5 weeks of RV hypertrophy. The compensatory remodeling in RV hypertrophy functionally restores the perfusion at the arteriolar and capillary level and wall shear stress in most of larger vessels. This is the first full analysis of coronary arterial tree, with millions of vessels, in cardiac hypertrophy that reveals the compensatory adaptation of structure to function.

L-NAME-induced hypertension has been shown to produce concentric (eutrophic) remodeling of the heart despite an enhanced afterload. We postulated that nitric oxide synthase inhibition could limit coronary capillary growth to explain the nature of remodeling. To test our hypothesis, we aimed at determining the effect of endogenous and exogenous nitric oxide on coronary neovascularization. Aortic and coronary rings from normotensive animals were incubated in a three-dimensional type I collagen matrix in the presence of L-NAME or the nitric oxide donor SNAP. L-NAME inhibited, while SNAP stimulated, neovascularization from aortic and coronary rings after 12 days of in vitro incubation. In arterial rings harvested from rats treated with L-NAME for 14 days and in which no further in vitro treatment was added, only coronary rings showed a reduction in new capillary generation. While confirming that chronic L-NAME-treated rats develop concentric remodeling, the evaluation of capillary density did not reveal any difference as compared with the controls in 3 areas of the myocardium. In conclusion, chronic inhibition of nitric oxide synthesis in vivo produces a long-lasting reduction in the capacity of coronary arteries to generate new capillaries in vitro. Thus, our results lend support to the hypothesis that an inhibition of new capillary formation could prevent the development of compensatory ventricular hypertrophy, in favor of concentric remodeling.

Introduction/purpose: We hypothesized that skeletal muscle histological and biochemical phenotypes aggregate within families., Methods: Nineteen families (78 Caucasians) from the HERITAGE Family Study participated in the study. Proportions and areas of Type I, IIA, and IIX muscle fibers, capillary density, and maximal enzyme activities were determined in biopsy samples from the vastus lateralis obtained in the sedentary state and after a 20-wk endurance-training program., Results: In the sedentary state, there was evidence for familial resemblance for Type I fiber area (P = 0.007), number of capillaries around Type I and Type IIA fibers (P = 0.04), and Type I and IIA fiber areas per capillary (P = 0.01 and P = 0.04, respectively). Significant familial aggregation (0.05>P > 0.0001) was observed for maximal activities of enzymes of the energy production pathways. With regard to the training response, significant familial aggregation (0.05 > P < 0.0001) was observed for maximal activities of enzymes of the energy production pathways., Conclusion: These data provide evidence of familial aggregation for enzyme activities of the main energy metabolism pathways of the skeletal muscle in the sedentary state and in response to regular exercise.

Background: Stromal cell-derived factor-1 (SDF-1) is a chemokine considered to play an important role in the trafficking of hematopoietic stem cells. Given the close relationship between hematopoietic stem cells and endothelial progenitor cells (EPCs), we investigated the effect of SDF-1 on EPC-mediated vasculogenesis., Methods and Results: Flow cytometric analysis demonstrated expression of CXCR4, the receptor of SDF-1, by 66+/-3% of EPCs after 7 days in culture. In vitro modified Boyden chamber assay showed a dose-dependent EPC migration toward SDF-1 (control versus 10 ng/mL SDF-1 versus 100 ng/mL SDF-1, 24+/-2 versus 71+/-3 versus 140+/-6 cells/mm2; P<0.0001). SDF-1 attenuated EPC apoptosis (control versus SDF-1, 27+/-1 versus 7+/-1%; P<0.0001). To investigate the effect of SDF-1 in vivo, we locally injected SDF-1 into athymic ischemic hindlimb muscle of nude mice combined with human EPC transplantation to determine whether SDF-1 augmented EPC-induced vasculogenesis. Fluorescence microscopic examination disclosed increased local accumulation of fluorescence-labeled EPCs in ischemic muscle in the SDF-1 treatment group (control versus SDF-1=241+/-25 versus 445+/-24 cells/mm2, P<0.0001). At day 28 after treatment, ischemic tissue perfusion was improved in the SDF-1 group and capillary density was also increased. (control versus SDF-1, 355+/-26 versus 551+/-30 cells/mm2; P<0.0001)., Conclusion: These findings indicate that locally delivered SDF-1 augments vasculogenesis and subsequently contributes to ischemic neovascularization in vivo by augmenting EPC recruitment in ischemic tissues.

Background: The progression of compensated hypertrophy to heart failure (HF) is still debated. We investigated patients with isolated valvular aortic stenosis and differing degrees of left ventricular (LV) systolic dysfunction to test the hypothesis that structural remodeling, as well as cell death, contributes to the transition to HF., Methods and Results: Structural alterations were studied in LV myectomies from 3 groups of patients (group 1: ejection fraction [EF] >50%, n=12; group 2: EF 30% to 50%, n=12; group 3: EF <30%, n=10) undergoing aortic valve replacement. Control patients were patients with mitral valve stenosis but normal LV (n=6). Myocyte hypertrophy was accompanied by increased nuclear DNA and Sc-35 (splicing factor) content. ACE and TGF-beta1 were upregulated correlating with fibrosis, which increased 2.3-, 2.2-, and 3.2-fold over control in the 3 groups. Myocyte degeneration increased 10, 22, and 32 times over control. A significant correlation exists between EF and myocyte degeneration or fibrosis. Ubiquitin-related autophagic cell death was 0.5 per thousand in control and group 1, 1.05 in group 2, and 6.05 per thousand in group 3. Death by oncosis was 0 per thousand in control, 3 per thousand in group 1, and increased to 5 per thousand (groups 2 and 3). Apoptosis was not detectable in control and group 3, but it was present at 0.02 per thousand in group 1 and 0.01 per thousand in group 2. Cardiomyocyte mitosis was never observed., Conclusions: These structure-function correlations confirm the hypothesis that transition to HF occurs by fibrosis and myocyte degeneration partially compensated by hypertrophy involving DNA synthesis and transcription. Cell loss, mainly by autophagy and oncosis, contributes significantly to the progression of LV systolic dysfunction.

Background: The phase difference of coronary arterial and venous flows indicates the importance of intramyocardial capacitance vessels in storing diastolic flow and in discharging volume in systole. However, the anatomic and functional characteristics of the capacitance vessels are unclear. We aimed to clarify those characteristics with their transmural difference by 3D visualization of transmural microvessels under diastole and systole., Methods and Results: We performed complete intracoronary filling of a contrast medium into Langendorff's Wistar rat hearts under (1) St Thomas-perfused diastolic arrest (D-mode) and (2) BaCl(2)-induced systolic arrest (S-mode). Precise transmural 3D architectures of capillaries and of pre- and post-capillary microvessels (ie, microvessels larger than capillaries) were visualized clearly with a confocal laser scanning microscope and x-ray microcomputed tomography (microCT), respectively. Vascular volume fraction (VF) and systolic-induced VF reduction rate from D- to S-mode were analyzed. The net capillary VF in D-mode (20.4 +/- 0.9%) was 10 times that of larger microvessels and was reduced in S-mode by 32% without capillary collapse. Systolic-induced VF reduction rate was smaller in capillaries than in larger microvessels (48%; P<0.05). The larger microvessel VF in D-mode (2.2 +/-0.2%) was reduced in S-mode, accompanied by complicated 3D deformation., Conclusions: Capillaries were relatively resistant to the systolic extravascular compression compared with pre- and post-capillary microvessels, conveniently beneficial for the myocardial oxygen delivery throughout a cardiac cycle. Nevertheless, a larger change in the absolute volume of capillaries may function as effective capacitance. On one hand, the pre- and post-capillary microvessels showed a larger phasic change in resistance, which may function to maintain the capillary patency during systole.

It has become of fundamental importance to understand variations in the shape of the upstroke of the action potential in order to identify structural loading effects. One component of this goal is a detailed experimental analysis of the time course of the foot of the cardiac action potential (Vm foot) during propagation in different directions in anisotropic cardiac muscle. To this end, we performed phase-plane analysis of transmembrane action potentials during anisotropic propagation in adult working myocardium. The results showed that during longitudinal propagation there was initial slowing of Vm foot that resulted in deviations from a simple exponential; corollary changes occurred at numerous sites during transverse propagation. We hypothesized that the effect on Vm foot observed in the experimental data was created by the microscopic structure, especially the capillaries. This hypothesis predicts that the phase-plane trajectory of Vm foot will deviate from linearity in the presence of a high density of capillaries, and that a linear trajectory will occur in the absence of capillaries. Comparison of the results of Fast and Kléber (Circ Res. 1993;73:914-925) in a monolayer of neonatal cardiac myocytes, which is devoid of capillaries, and our results in newborn ventricular muscle, which is rich in capillaries, showed drastic differences in Vm foot as predicted. Because this comparison provided experimental support for the capillary hypothesis, we explored the underlying biophysical mechanisms due to interstitial electrical field effects, using a "2-domain" model of myocytes and capillaries separated by interstitial space. The model results show that a propagating interstitial electrical field induces an inward capacitive current in the inactive capillaries that causes a feedback effect on the active membrane (source) that slows the initial rise of its action potential. The results show unexpected mechanisms related to extracellular structural loading that may play a role in selected conduction disturbances, such as in a reperfused ischemic region surrounded by normal myocardium.

A thick endothelial surface coat consisting of the glycocalyx and associated plasma proteins has been hypothesized to reduce functional capillary volume available for flowing plasma macromolecules and blood cells. The purpose of this study was to compare anatomic and functional capillary diameters available for macromolecules, RBCs, and WBCs in hamster cremaster muscle capillaries. Bright-field and fluorescence microscopy provided similar estimates (mean +/- SE) of the anatomic capillary diameter: 5.1 +/- 0.1 microns (bright field, 39 capillaries in 10 animals) and 5.1 +/- 0.2 microns (membrane dye PKH26, 18 capillaries in 2 animals). Estimates of functional diameters were obtained by measuring the width of RBCs and WBCs and the intracapillary distribution of systemically injected fluorescein isothiocyanate (FITC)-dextran 70. WBCs (5.1 +/- 0.2 microns) fully occupied the anatomic capillary cross section. In contrast, the widths of RBCs (3.9 +/- 0.2 microns, 21 capillaries in 8 animals) and FITC-dextran (4.3 +/- 0.2 microns, 21 capillaries in 8 animals) were significantly smaller than the anatomic capillary diameter. Continuous (1- to 5-minute) excitation of fluorochromes in the capillary lumen (light-dye treatment) increased the width of RBCs passing the treated site from 3.6 +/- 0.3 to 4.4 +/- 0.3 microns (6 capillaries in 4 animals) and the width of the FITC-dextran column from 4.1 +/- 0.2 to 4.6 +/- 0.3 microns (10 capillaries in 7 animals). Furthermore, light-dye treatment increased capillary tube hematocrit by 60% in 40-microns-long capillary segments compared with untreated sites in the same capillaries. It is concluded that the wall of skeletal muscle capillaries is decorated with a 0.4- to 0.5-microns-thick endothelial surface coat, which may represent the true active interface between blood and the capillary wall.

Study Design: Vascular buds in rabbit vertebral endplates were examined by scanning electron microscopy of corrosion casts., Objectives: To examine morphologic differences between vascular buds in two regions of the vertebral endplate (inner anular and nucleus pulposar)., Summary of Background Data: Vascular buds are specific structures present at the vertebral endplate that are important as nourishing channels. There is a significant difference in permeability between the lateral portion (inner anular) and the central portion (nucleus pulposar) of the endplate, the latter usually being permeable and the former being impermeable. Morphologic differences between vascular buds in the two regions have not been investigated previously., Methods: Eight 20-week-old rabbits were used. Vascular buds in rabbit vertebral endplates were examined by scanning electron microscopy of corrosion casts., Results: The vascular buds in the region of the inner anulus form simple loops, but those in the area near the nucleus pulposus exhibit swollen and complex coil-like loops. Although they differ structurally, the average number of vascular buds per area does not vary between the two regions., Conclusions: We suggest that the morphologic difference between the vascular buds in the two regions (inner anular and nucleus pulposar) plays a principal role in permeability at the endplate.

Numerous studies have examined the effects of exercise training on coronary angiogenesis. Although the conclusions drawn from these studies are sometimes conflicting, variabilities in training (magnitude, type and intensity), age and other factors need to be closely examined. Most studies on young animals indicate that capillary growth occurs providing that the training intensity is appropriate. Furthermore, there is evidence that growth of arteries and resistance vessels can occur as indicated by 1) direct measurements of vessels and 2) calculation of minimal coronary vascular resistance during pharmacologically induced vasodilation. Although the mechanism(s) underlying exercise-induced angiogenesis is unknown, mechanical events associated with increased flow and/or increased venous return, as well as resting bradycardia may serve to trigger growth factors involved in mitogenic, migratory, and tube formation of endothelial cells. In contrast, exercise training per se does not appear to enhance collateral vessel growth. However, there is evidence that collateral growth is accelerated with training in animals with coronary artery occlusion.

Confocal laser-scanning microscopy was used to visualize subsurface cerebral microvessels labeled with intravascular fluorescein in a closed cranial window model of the anesthetized rat. In noninvasive optical sections up to 250 microns beneath the brain surface, plasma perfusion and blood cell perfusion of individual capillaries were studied. Under resting conditions, in all cerebral capillaries the presence of plasma flow as demonstrated by the appearance of an intravenously injected fluorescent tracer within 20 seconds after injection. Plasma flow was verified even in capillaries that contained stationary erythrocytes or leukocytes; 91.1% of the capillaries contained flowing blood cells, 5.2% contained stationary blood cells, and no blood cells were seen in 3.6%. Mean blood cell velocity was 498.3 +/- 443.9 microns/s, and the mean blood cell supply rate was 35.75 +/- 28.01 cells per second. When capillaries were continuously observed for 1 minute, "on" and "off" periods of blood cell flow were noted. During hypercapnia (increase of PCO2 from 33.25 to 50.26 mm Hg), mean blood cell flux increased from 38.6 +/- 17.2 to 55.5 +/- 12.2 per second (P < .005, paired t test of mean values in six animals), and blood cell velocity increased from 519.5 +/- 254.8 to 828.5 +/- 460.8 microns/s (P = .074, paired t test of mean values in six animals). Homogeneity of blood cell flux increased as indicated by the coefficient of variation decreasing from 44.6% to 22.0%, and the portion of poorly perfused capillaries (blood cell flux, < 40 per second) decreased from 59.2% to 22.4%.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this work is to expand the knowledge about fiber distribution, capillarization, and metabolic potential in different anatomic sections of the left and right human lumbar paravertebral muscles and further to investigate whether a relationship between these parameters and trunk muscle endurance exists. Lumbar (L3) paravertebral muscle samples were taken bilaterally from six young male cadavers (study 1) and from 10 normal young healthy men (study 2). The main findings are that the paravertebral muscles are dominated by slow twitch fibers with small fiber areas and a well-developed capillary network. This is most pronounced in the longissimus muscle. Glycogen concentration and enzyme activities (glycogen phosphorylase, lactate dehydrogenase, citric synthetase and 3-hydroxyacyl-CoA-dehydrogenase) in both aerobic and anaerobic metabolic pathways are large compared to other muscles. No obvious bilateral differences in the histochemical and biochemical results were present. The isometrical trunk extensor endurance time is markedly increased compared to other human skeletal muscles.

To explore a mechanism for spatial recruitment of capillaries, this study determined whether the arterioles controlling capillary perfusion, which typically arise as sequential branches along a transverse arteriole, could respond differently from each other in situ in a spatially ordered way. Diameter changes were measured for these arterioles at a known location in the intact microvasculature in the cremaster muscle of anesthetized Golden hamsters (N = 67); each arteriole controls separate capillary groups. These arterioles all had the same concentration dependence to locally (by micropipette) applied norepinephrine (NE, 10(-9) to 10(-3) mol/L), and 10(-9) mol/L NE did not induce diameter changes when applied locally to individual vessels. However, 10(-9) mol/L NE added to the tissue superfusate, or 5% added superfusate oxygen (also locally subthreshold), each induced significant diameter changes (both constrictions and dilations), in different branches, that were presumably due to summation of individually subthreshold events that changed the prevailing conditions at the point of observation. These significant diameter changes were related to the maximal diameter or to initial tone of the branches, but these changes occurred in different ways for NE versus oxygen. With NE, the branch arterioles that constricted (versus dilated) were significantly larger (maximal diameter, 22.3 +/- 2.6 versus 15.9 +/- 2.1 microns) and had higher tone (fractional constriction, 0.53 +/- 0.05 versus 0.63 +/- 0.05); with oxygen, those that constricted were the same size as those that dilated (maximal diameter, 28.6 +/- 1.1 versus 30.5 +/- 2.7 microns), but constrictors had lower tone (fractional constriction, 0.49 +/- 0.04 versus 0.39 +/- 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)

Capillary-to-fiber geometrical relations constitute an integral component of peripheral gas exchange. Determination of capillary length and surface area density necessitates quantification of capillary orientation (i.e., tortuosity and branching). In skeletal muscle, capillary tortuosity increases in a curvilinear fashion at reduced sarcomere length, and this compensates for decreased capillary density as fiber cross-sectional area increases. To investigate these relations in myocardium, rat hearts were glutaraldehyde perfusion-fixed in calcium- or barium-induced "systole" to provide varying degrees of fiber shortening. Morphometric techniques were used to analyze capillary geometry in subepicardium (EPI) and subendocardium (ENDO) using 1-micron sections cut transverse and longitudinal to the muscle fiber axis. Capillary density on transverse and longitudinal sections, capillary diameter, fiber cross-sectional area, and sarcomere length were determined in each region. Capillary surface density was computed, and values were related to sarcomere length and compared with published data for diastolic hearts. Sarcomere length in systole ranged from 2.06 +/- 0.03 to 1.35 +/- 0.02 microns (EPI) and from 1.93 +/- 0.04 to 1.44 +/- 0.04 microns (ENDO). Fiber cross-sectional area (EPI, 344 +/- 13 microns2; ENDO, 343 +/- 12 microns2) was significantly larger, and capillary density on transverse sections was significantly smaller (EPI, 4,105 +/- 318 mm-2; ENDO, 4,145 +/- 267 mm-2) than in hearts arrested in diastole. Compared with skeletal muscle, capillary tortuosity was substantially less increased by fiber shortening. Capillary tortuosity and branching did not differ between EPI and ENDO and contributed a maximum of 33% (range, 13-33%) to capillary length density and surface area at a sarcomere length of 1.45 +/- 0.04 microns. Compared with diastolic hearts, capillary length density decreased on average by 19.6% (EPI) and 17.7% (ENDO); similarly, capillary surface density decreased 19.9% (EPI) and 13.7% (ENDO). We conclude that, with fiber shortening in the heart, fiber cross-sectional area increases and capillary numerical density decreases as predicted from reduced sarcomere length. Combined with the minimal geometrical changes of the capillary bed at shorter fiber lengths, this results in a lower capillary length and surface area per fiber volume in systole. Consequently, the structural potential for O2 diffusion into myocytes is determined, in part, by fiber length.

The geometry of capillary networks was examined in pressure-overloaded hypertrophic rat myocardium. All hearts were exposed to a staining protocol that distinguished the arteriolar (AC) and venular (VC) regions of capillaries. In control hearts, the triangulation method (one-dimensional distance between neighboring capillaries) and the domain method (two-dimensional area surrounding capillaries) exhibited similar results, showing increased capillarization for the venular region of capillaries networks. In hypertrophic hearts, the triangulation method did not demonstrate differences between arteriolar and venular capillaries (AC = 27.2 +/- 0.4 microns, VC = 27.0 +/- 0.2 microns, p = 0.56). However, the domain method still detected smaller tissue supply regions for venular capillaries (AC = 547 +/- 6 microns 2, VC = 464 +/- 5 microns 2, p less than 0.01). To resolve this discrepancy in hypertrophic heart, we have measured capillary spacing from longitudinal sections at discrete intervals along the A-V path length. These results indicate a stepwise decrease in intercapillary distance from arteriole to venule for both groups, which would support results obtained by the domain method. A possible explanation for the discrepancy between these two methods, specific to hypertrophic heart, may be changes in the clustering patterns of arteriolar and venular capillaries.

Pain block in obstetric epidural anesthesia is usually accompanied by relatively persistent retention of motor power; however, the reason for this is not entirely clear. The differential effect has been ascribed to a relatively high resistance of large fibers to conduction block. However, recent results from individual axons are incompatible with that explanation and have prompted the suggestion that greater vascularity in ventral than in dorsal roots might account for the phenomenon. To test this hypothesis, transverse sections of five sets of human dorsal and ventral C-8, T-7, and L-5 roots were examined by an immunohistochemical method that is specific for factor VIII and stains the vascular endothelium. A naive tally of the stained vessels failed to reveal any excess vascularity of the ventral roots, and the hypothesis was therefore rejected. However, it was noted at autopsy that the thin dural sleeve surrounding the roots, where epidural anesthetic is most likely to penetrate to the nerve fibers, may measure less than 5 mm from the dural sac to the intervertebral foramen, a distance probably too short to contain three internodes of motor fibers, the minimum length of fiber necessary for block by local anesthetic. This anatomy might help explain the clinical differential.

We studied 10 autopsied human hearts by perfusing colored Microfil into separate coronary arteries to define organization of capillaries at the borders between two perfusion fields. Sections of "cleared" myocardium were examined with epiillumination at the grossly identified borders of Microfil perfusion. In two- and three-color-injected hearts, the capillaries were arrayed in a pattern of arcades and loops without connections between separately perfused capillary beds. In hearts perfused through only one coronary artery, the capillaries were organized into tufted loops at the border. These findings contrast with the microcirculatory pattern in canine skeletal muscle and brain, in which heterologous capillaries are focally interconnected. We conclude that the human microcirculation is composed of end-capillary loops that supply discrete perfusion fields. This pattern of unconnected heterologous capillary beds suggest that there is no obvious anatomic arrangement of the microcirculation that could account for a significant ischemic lateral border zone in human myocardial infarctions.

The vascularity of the facial canal in the rat was studied with the microcorrosive technique and scanning electron microscopy. The vascular casts thus created demonstrated the larger feeding vessels and the extrinsic vascular supply, but gave above all a good three-dimensional comprehension of the fine blood vessels within the nerve proper, the intrinsic vascular supply. The facial nerve is supplied by a rich anastomosing network of these fine blood vessels. Vascular loops and arteriovenous anastomoses are common, thus avoiding the creation of end-arterial systems. The blood vessels of the facial nerve also communicate widely with the rest of the temporal bone through small bony canals present in the lining of the facial canal. The architecture and distribution of the fine blood vessels are of great clinical interest, especially with regard to the etiology of idiopathic peripheral facial palsy, since it is at this level that the exchange of fluids, elecrolytes, and metabolites takes place.

The purpose of the present study was to evaluate the effects of iron deficiency on enzyme activities and endurance. Iron deficiency was induced in 9 healthy male subjects by repeated venesections. After a period of 9 wk (range, 8-11 wk) when the subjects had become iron deficient as defined by laboratory parameters, blood was retransfused to reestablish the control hemoglobin concentration. In this state it was possible to evaluate the effect of iron deficiency isolated from anemia. In samples secured by muscle biopsies, glycolytic, oxidative, and iron depending enzymes were analyzed in the control (C) and anemic (A) states and after retransfusion (R). There were no significant changes in the maximal activities of any of the enzymes studied. The capillary/fiber ratio remained unchanged between C (1.92) and R (1.94). Times to exhaustion on treadmill tests were 49 min, 11 s in C, 26 min, 33 s in A, and 52 min, 3 s in R. Vo2max was 4.55 1 X min-1 in C, 3.74 1 X min-1 in A, and 4.45 1 X min-1 in R. An artificially induced iron deficiency defined by conventional laboratory parameters did not affect endurance when transfusion of red blood cells was performed in order to exclude the influence of a low hemoglobin concentration. A 4-wk period of severely depleted or absent tissue iron stores did not affect the maximal activities of various enzymes in human skeletal muscle.

The homozygous (hr/hr) hairless mouse ear was introduced in 1980 by Eriksson and coworkers as a model for in vivo studies of the skin microcirculation. Herein we expand on this work, presenting results of in vivo microvascular parameter measurements and morphologic studies in the intact ear. The in vivo measurements include microvascular diameter, RBC velocity, capillary density, and the frequency and amplitude of arteriolar vasomotion. In connection with the in vivo studies, a detailed anatomic description of the overall and vascular anatomy is given. Additionally, the preparation techniques for carrying out these in vivo and morphologic studies in the mouse ear are presented in detail.

In our morphometric study of the effects of exercise on the heart, male Wistar-Kyoto rats at 5 weeks of age were subjected daily to a moderate treadmill running program that lasted for 7 weeks. The heart responded to physical conditioning by different magnitudes of tissue growth of the right (22%) and left (7%) ventricular myocardium, the latter change not statistically significant. The increase in right ventricular volume was associated with a 25% enlargement of ventricular area, a 26% average lengthening of the myocytes, and no change in sarcomere length and in ventricular midwall thickness. Exercise produced significant alterations in the quantitative parameters of the microvasculature of the right ventricle, but no appreciable changes in the left ventricle. Right ventricular hypertrophy was characterized by an absolute 44% growth of the endothelial luminal surface brought about through a 16% increase in capillary numerical density, and a 41% augmentation of the total length of the capillary network. Maximum diffusion distance from the capillary wall to the mitochondria of myocytes decreased 10% as a result of capillary proliferation and the lack of lateral expansion of myocyte cross-sectional area. Evaluation of the subcellular constituents of myocytes showed no change in the mitochondria:myofibrils volume ratio, indicating a growth of these components proportional to each other and to the growth of the myocyte population as a whole. It was concluded that, as a result of running exercise, right ventricular growth is analogous to eccentric hypertrophy in which the structural adaptations of the capillary bed can be expected to improve the diffusion and transport of oxygen within the tissue.

In order to study the detailed arrangements of vascular terminations in the region of the vertebral end-plate in adult dogs, infusions of Japanese ink mixed with a suspension of barium sulfate were used to produce filling of the vascular terminations at the vertebral end-plates. Radiographs were made of the decalcified specimens. Photomicrographs were prepared from transparent sections embedded in celloidin. The distribution of the large veins within the vertebral bodies was found to be more complex than described earlier. Over the entire bone-disc interface there is a continuous capillary bed that is most dense in the area related to the nucleus pulposus. These vessels drain either into the subchondral postcapillary venous network or directly into the veins of the marrow spaces in the vertebral bodies.

Morphological studies have demonstrated an age-related decrease in capillary density and capillary surface area in the developing heart. However, the consequences of these changes on myocardial perfusion are not known. We tested the hypothesis that the decreased capillary density is associated with a reduction in coronary blood flow reserve. To test this hypothesis, we studied coronary responses to adenosine and sodium nitroprusside administration, reactive hyperemia, and autoregulatory capacity. We used a Langendorff-perfused heart preparation from guinea pigs of five different age groups (1 week and 1, 2, 12, and 18 months). Data are expressed as mean +/- SEM. Maximal coronary flows (ml/min per g) in response to adenosine (10(-6) to 10(-5) M) infusion are: 27 +/- 1.3, 18.5 +/- 1.4, 12.2 +/- 0.4, 10.3 +/- 0.3, and 10.6 +/- 0.8 at 1 week, 1, 2, 12, and 18 months, respectively, with the flows at 1 week and 1 month significantly higher than those at 2, 12, and 18 months. There is a similar trend for a decreased maximum coronary perfusion in response to sodium nitroprusside (10(-6) to 10(-5) M) and following a 45-second occlusion of the coronary inlet flow. Despite the decreased maximal pharmacological and reactive hyperemic flow reserve, autoregulation of flow is not altered with growth. The pressure-flow relationship exhibits autoregulation between 25 and 55 mm Hg perfusion pressure for all but the 1-week age group, which autoregulates within a narrower range of pressures (20-45 mm Hg). Total maximal coronary flow (ml/min) increases during development; this indicates that the growth of vessels continues with development.(ABSTRACT TRUNCATED AT 250 WORDS)

The homozygous hairless mouse ear provides a reproducible model for the study of the microcirculatory changes of the burn wound during and following a scald burn injury. This model has allowed us to correlate the dynamic changes of the microcirculation to progressive zones of injury, which show an approximate tenfold increase in the area of complete capillary occlusion during the first 48 hours after injury. Platelet thromboembolism appears to be the major factor causing this progression of postburn dermal ischemia. Edema (increased skin water content) was greatest in the burned ear at 6 hours after the burn (20 percent greater than control values); edema of the unburned, contralateral ear was significant at 2 hours after the burn (9 percent greater than control values).

Recent studies show that acute and chronic hyperglycemia cause a diffuse decrease in regional cerebral blood flow and that chronic hyperglycemia decreases the brain L-glucose space. Since these changes can be caused by a decreased density of perfused brain capillaries, we used 30 adult male Wistar rats to study the effect of acute and chronic hyperglycemia on 1) the brain intravascular space using radioiodinated albumin, 2) the anatomic density of brain capillaries using alkaline phosphatase histochemistry, and 3) the fraction of brain capillaries that are perfused using the fluorescein isothiocyanate-dextran method. Our results indicate that acute and chronic hyperglycemia do not affect the brain intravascular space nor the anatomic density of brain capillaries. Also, there were no differences in capillary recruitment among normoglycemic, acutely hyperglycemic, and chronically hyperglycemic rats. These results suggest that the shrinkage of the brain L-glucose space in chronic hyperglycemia is more likely due to changes in the blood-brain barrier permeability to L-glucose.

Blood flow in vasa recta capillaries of the exposed renal papilla of young antidiuretic rats (n = 18) was determined by an adaptation of the video-photometric technique of Intaglietta. The erythrocyte velocity and capillary diameter in vasa recta (n = 97) were measured at the same location by means of fluorescence video microscopy, with fluorescein-labeled bovine gamma-globulin as a plasma marker. A factor relating erythrocyte velocity to mean cross-sectional blood velocity was determined in vitro to permit the calculation of single vasa recta blood flows from the measured indices, erythrocyte velocity and capillary diameter. Mean blood flow in descending vasa recta was 8.83 +/- 0.96 (SE) nl/min, significantly greater than that in ascending vasa recta, 4.82 +/- 0.34 nl/min. The total numbers of ascending and descending vasa recta at the base of the exposed papilla were also determined. Over 1500 vasa recta were identified as ascending vasa recta or descending vasa recta in electron micrographs of three papillas. At this level in the papilla (2 mm from the tip), there were four ascending vasa recta for each descending vas rectum. From the total numbers of ascending vasa recta and descending vas rectum, single vessel blood flows were converted to total blood flow. Total blood outflow in all ascending vasa recta, 11.3 microliter/min, substantially exceeded total blood inflow in all descending vasa recta, 5.2 microliter/min. The difference between outflow and inflow (6.1 microliter/min) represents an estimate of water by the papillary microcirculation, and is more than adequate to accommodate the known rate of water reabsorption from the collecting ducts of the exposed papilla.

There are two barriers between the blood and retina--one in the retinal circulation at the endothelial cell lining with its tight junctions in the retinal capillaries, and the second involving the choroidal circulation at the zonula occludens between adjacent retinal pigment epithelial cells. Damage to either of these barriers results in a leakage of fluid into or beneath the sensory retina. Serous detachment of the retinal pigment epithelium is a special situation in which both barriers remain intact but fluid accumulates in the space between the detached pigment epithelial cells and Bruch's membrane. It is convenient to analyze the fluorescein angiographic findings in relation to these two barriers, as a large number of retinal disorders affect either the retinal vascular system or the choriocapillaris-Bruch's membrane-pigment epithelium layers.

From a resin cast of a normal pulmonary arterial tree, the diameter, length, and number of branches in each order were determined for arteries from 25 to 300 micrometer in diameter. Histological sections 120-micrometer thick were cut from a normal human lung in which the pulmonary artery had been injected with a mixture of ink and gelatin. Similar measurements were made on arteries from 10 to 70 micrometer in diameter, and the mode of origin of the capillaries was studied. The data thus obtained were found to correspond reasonably well to values previously estimated by extrapolation from data for arteries of 100 micrometer or more in diameter. The branching rules apply down to arteries of about 10-15 micrometer in diameter, the estimated number of which is 73 million. Distal to these vessels, capillaries arise either directly from small arteries or indirectly via precapillaries which are given off in great numbers and diverse patterns from the small arteries

We made simultaneous measurements of intravascular pressure and red blood cell velocity for vessels which make up the modular configuration of microvascular networks in mesentery and omentum. An analysis of these variables and the computed volumetric flow rates is presented for arterioles which had a maximum diameter of 56 micrometer through the "true capillaries" (typically 7 micrometer for mesentery and 8 micrometer for omentum) to 56-micrometer venules. The spatial variance of pressure and flow is related to topographical features of each network. Vascularization statistics for each network are presented and demonstrate a unique ratio of potential microvascular exchange area to module planar area, with values of 0.71 +/- 0.22 (SD) for omentum and 0.19 "/- 0.03 (SD) for mesentery. Analysis of the volumetric flow rate for each module demonstrates a linear relationship to the planar area of tissue serviced by each modular network. In situ perfusion rates of 1180 ml/min per 100 g and 105 ml/min per 100 g were determined for omentum and mesentery, respectively. The hemodynamic resistance of the omental and mesenteric circuitry was evaluated, and in the case of the omentum, found to be inversely proportional to the planar area of the module. The arterial to venous distribution of pressure and flow for the mosaic of contiguous modules in omentum and mesentery is described and related to the deployment of parallel and serial microvessels of each network.

A concern for the possible role of the blood-brain barrier (BBB) in the epilepsies was based on ultrastructural studies that demonstrated increased micropinocytosis in cerebral capillaries during seizures. Continued interest in the structure of the BBB has led to the demonstration that, in human psychomotor epilepsy, there is a thickening of the capillary basement membrane. These studies also suggest that an increase in capillary mitochondria and interendothelial tight junctions may characterize seizure-traumatized brain regions. These studies forecast an increased interest and understanding of the ultrastructural events associated with capillaries in seizure states. Additional focus on the BBB comes from the clinical use of anticonvulsant drug levels in the control and treatment of seizures. Debate as to whether free drug levels are appropriate continues. The brain capillary is the interface between blood-borne drug and the target site, and thus an increased understanding of the events associated with brain-plasma exchange has been sought. The concept that only that fraction of drug that is freely dialyzable is available for equilibration across the BBB is not supported by recent studies, which demonstrate that protein-bound ligands are able to dissociate and gain access to the brain in the course of a single capillary transit. It has been established that albumin-bound fatty acids, steroids, and anticonvulsant drugs more readily distribute into tissues than previously believed. Thus, traditional free drug hypotheses need to be expanded to account for the fact that dissociation constants measured in vitro are not the same as those measured in vivo. The BBB also regulates nutrient availability to the brain, and under normal conditions excess substrate is made available to the brain for metabolism. Indirect evidence is available to suggest that during seizures, BBB transport may indeed be the rate-limiting step. Specifically, glucose availability to the seizing brain may be restricted to such a degree that brain glucose utilization rates are no longer independent of plasma glucose levels. If it can be proven that BBB transport is the rate-limiting step during seizures, then it would be possible to augment brain glucose utilization rates by increasing plasma glucose levels. In addition, a depression of brain glucose utilization could be achieved by inducing hypoglycemia. It is not fully understood whether BBB rate limitation would persist postically, nor is it known whether BBB alterations may be global or restricted to the seizure focus.(ABSTRACT TRUNCATED AT 400 WORDS)

Quantitative study of the capillary density of normal dermis of 113 biopsy specimens taken from 20 body sites from 6 cadavers was carried out. Histologic quantification of dermal capillaries using the alkaline phosphatase method to delineate vascular endothelium and automated image analysis demonstrates statistically significantly greater capillary density in the head-face/neck region both in the papillary and reticular dermis than in the lower parts of the body. The smallest numbers of the dermal capillary density were noted in the calf and shin areas. These data support the hypothesis that random-pattern skin flaps can be safely raised longer in the face and neck than in other parts of the body.

Fenestrated capillaries are provided with two types of regular discontinuities: fenestrae with negatively charged diaphragms, and transendothelial channels fitted with two diaphragms, of which the luminal one is uncharged. These structures are expected to affect macromolecular exchanges on the basis of size and charge. We have detected variations in the surface density of fenestrations and transendothelial channels (normalized to 1 micron of capillary endothelial profiles in sections) in selected areas of different murine organs, i.e., kidney cortex, duodenal mucosa, and exocrine pancreas. The survey was limited to endothelial segments less than or equal to 400 nm thick, and covered a total length of endothelial profiles of 1180 microns, 730 microns, and 1189 microns in the exocrine pancreas, intestinal mucosa, and kidney cortex, respectively. At least 1000 transendothelial openings were recorded by scoring for easily recognizable fenestrations, transendothelial channels, and unknowns, the latter representing either of the above in grazing sections. The linear density of all transendothelial openings taken together was found to vary among the different capillary beds (kidney cortex greater than intestinal mucosa greater than exocrine pancreas). This same sequence was observed for the linear densities of fenestrations, transendothelial channels, and unknowns considered individually. The values obtained were as follows: kidney cortex, 1.35 fenestrations per micron, 0.25 transendothelial channels per micron, 0.52 unknowns per micron; intestinal mucosa, 0.92 fenestrations per micron, 0.10 transendothelial channels per micron, 0.38 unknowns per micron; exocrine pancreas, 0.58 fenestrations per micron, 0.04 transendothelial channels per micron, 0.27 unknowns per micron. The differences in distribution of transendothelial openings among fenestrated capillary beds probably reflect capillary permeability modulations connected with the functions of these various organs.