Angiotensin converting enzyme inhibition enhances collateral artery remodeling in rats with femoral artery occlusion.

Evidence from experimental animal studies indicate that ACE inhibition expands collateral blood flow both in ischemic hearts and peripheral limbs. The present study evaluates whether ACE inhibitor induces collateral blood flow expansion and change of angiogenic gene expression profile in collateral arteries during remodeling. Male Sprague-Dawley rats, weighing 350 g were treated with vehicle (control) or quinapril (ACE inhibitor) at either low dose (3.0 mg/kg) or high dose (18 mg/kg) for 1, 3, 7, 14 days (gene expression) or 16 days (blood flow). All rats received bilateral occlusions of the femoral arteries. Collateral blood flow to the hind limb was assessed by 85Sr and 141Ce-labeled microspheres during treadmill running at 15 and 25 m/min speeds. Quinapril reduced plasma ACE activity by 58% and 88% for the low-dose and high-dose groups, respectively (P < 0.001). High-dose quinapril reduced exercising blood pressure (P < 0.05) and increased hind limb conductance. Collateral blood flows to calf muscles were 51 +/- 3.7, 73 +/- 5.0, and 68 +/- 1.9 mL/min per 100 g in control and quinapril low- and high-dose groups, respectively, during high-speed running (P < 0.001). Real-time RT-PCR revealed that ACE inhibition shifted gene expression to a proangiogenic phenotype in the newly developed collateral arteries. Our findings indicate that ACE inhibition could increase collateral-dependent blood flow and collateral vessel remodeling by promoting proangiogenic gene expression in newly developed collateral arteries. Our results support the potential utility of ACE inhibitor as a therapeutic agent in treating peripheral occlusive arterial disease.

Skinfold prediction equation for athletes developed using a four-component model.

INTRODUCTION: Skinfold (SKF) equations exist to predict percent body fat (%BF) in athletes; however, none have been derived from multicomponent model reference measures. PURPOSE: To develop and cross-validate a %BF prediction equation based on SKF in athletes using a four-component model as the reference measure. METHODS: Subjects were 132 collegiate athletes (20.7 +/- 2.0 yr; 78 males: 28 black, 50 white; 54 females: 10 black, 44 white). Four-component model estimates of %BF (%BF4C) included measures of total body water from deuterium dilution, bone mineral by dual- energy x-ray absorptiometry (DXA), and body density by densitometry using underwater weighing. SKF measures included subscapular, triceps, chest, midaxillary, suprailiac, abdominal, and thigh sites (7SKF). A prediction equation was developed on 102 athletes using 7SKF, race, and gender as predictor variables. Cross-validation was performed on a representative holdout sample of 30 athletes. RESULTS: The equation cross-validated well (slope and intercept both not different (P > 0.05) from the line of identity (LOI); r(YY') = 0.85, total error (TE) = 3.76%BF) and was better than the existing athlete SKF equations (intercept and slope both different from LOI (P < 0.01); r(YY') = 0.76, TE = 4.51%BF). Notably, a prediction equation developed using 3SKF sites (abdomen, thigh, and triceps) produced a similar accuracy (intercept and slope both not different from LOI (P > 0.05); r(YY') = 0.85, TE = 3.66%BF). CONCLUSIONS: The new 7SKF equation improved on SKF equations developed using densitometry. The final equation based on the whole sample was %BF' = 10.566 + 0.12077*(7SKF) - 8.057*(gender) - 2.545*(race). Moreover, a 3SKF equation was comparable in accuracy to the 7SKF equation: BF' = 8.997 + 0.24658*(3SKF) - 6.343*(gender) - 1.998*(race).

A mathematical method to estimate body composition in tall individuals using DXA.

PURPOSE: The purpose of this investigation was to determine whether whole body composition could be estimated in tall individuals using summed measures from two partial DXA scans. METHODS: Using a pencil-beam DXA, a convenience sample of young individuals (N = 19) were scanned three times. Two partial scans of the upper and lower body were combined to predict bone area, bone mineral content (BMC), bone mineral density (BMD), fat mass (FM), fat-free soft tissue mass (FFST), and percent fat (%Fat), from a complete whole body scan. Two different methods, dividing the body at the hip (HIP) or at the top of the shoulders (NECK), were used to determine optimal method of summing. RESULTS: There were no significant differences in BMC, BMD, FM, FFST, and %Fat comparing the complete scan and summed scans regardless of summing method. There was excellent agreement between complete and summed values of BMC, BMD, FM, FFST, and %Fat values as indicated by regression analysis (r value range: 0.992-1.00) and nonsignificant intercepts. Bland-Altman plot analysis indicated that a small systemic bias occurred in estimates of FM and %Fat using the HIP method and FFST using the NECK method; however, all biases were negligible. CONCLUSIONS: The findings suggest that accurate estimates of whole body composition from a complete scan can be obtained by summing two partial scans. Although both summing methods provide good estimates of body composition, dividing the body at the neck provides more accurate estimates of bone and soft tissue composition than dividing the body at the hip.

VEGF receptor antagonism blocks arteriogenesis, but only partially inhibits angiogenesis, in skeletal muscle of exercise-trained rats.

Both collateral vessel enlargement (arteriogenesis) and capillary growth (angiogenesis) in skeletal muscle occur in response to exercise training. Vascular endothelial growth factor (VEGF) is implicated in both processes. Thus we examined the effect of a VEGF receptor (VEGF-R) inhibitor (ZD4190, AstraZeneca) on collateral-dependent blood flow in vivo and collateral artery size ex vivo (indicators of arteriogenesis) and capillary contacts per fiber (CCF; an index of angiogenesis) in skeletal muscle of both sedentary and exercise-trained rats 14 days after bilateral occlusion of the femoral arteries. Total daily treadmill run time increased appreciably from approximately 70 to approximately 100 min (at 15-20 m/min, twice per day) and produced a large (approximately 75%, P < 0.01) increase in calf muscle blood flow and a greater size of the collateral artery (wall cross-sectional area). ZD4190, which previously has been shown to inhibit the activity of VEGF-R2 and -R1 tyrosine kinase in vitro (IC50 = 30 and 700 nM, respectively), completely blocked the increase in collateral-dependent blood flow and inhibited collateral vessel enlargement. Thus exercise-stimulated collateral arteriogenesis appears to be completely dependent on VEGF-R signaling. Interestingly, enhanced mRNA expression of the VEGF family ligand placental growth factor (2- to 3.5-fold), VEGF-R1 (approximately 2-fold), and endothelial nitric oxide synthase (2- to 3.5-fold) in an isolated collateral artery implicates these factors as important in arteriogenesis. Training of ischemic muscle also induced angiogenesis, as shown by an increase (approximately 25%, P < 0.01) in CCF in white gastrocnemius muscle. VEGF-R inhibition only partially blocked (P < 0.01) but did not eliminate the increase (P < 0.01) in capillarity. Our findings indicate that VEGF-R tyrosine kinase activity is essential for collateral arteriogenesis and important for the angiogenesis induced in ischemic muscle by exercise training; however, other angiogenic stimuli are also important for angiogenesis in flow-limited active muscle.

What makes vessels grow with exercise training?

Exercise and muscle contractions create a powerful stimulus for structural remodeling of the vasculature. An increase in flow velocity through a vessel increases shear stress, a major stimulus for enlargement of conduit vessels. This leads to an endothelial-dependent, nitric oxide-dependent enlargement of the vessel. Increased flow within muscle, in the absence of contractions, leads to an enhanced capillarity by intussusceptive angiogenesis, a process of capillary splitting by intraluminal longitudinal divide. In contrast, sprouting angiogenesis requires extensive endothelial cell proliferation, with degradation of the extracellular matrix to permit migration and tube formation. This occurs during muscle adaptations to chronic contractions and/or muscle overload. The angiogenic growth factor VEGF appears to be an important element in angiogenesis. Recent advances in research have identified hemodynamic and mechanical stimuli that upregulate angiogenic processes, demonstrated a complexity of potent growth factors and interactions with their corresponding receptors, detected an interaction of cellular signaling events, and identified important tissue reorganization processes that must be coordinated to effect vascular remodeling. It is likely that much of this information is applicable to the vascular remodeling that occurs in response to exercise and/or muscle contractions.

Time course of changes in collateral blood flow and isolated vessel size and gene expression after femoral artery occlusion in rats.

The objectives of this study were to assess the time course of enlargement and gene expression of a collateral vessel that enlarges following occlusion of the femoral artery and to relate these responses to the increases in collateral-dependent blood flow to the calf muscles in vivo. We employed exercise training to stimulate collateral vessel development. Rats were exercise trained or kept sedentary for various times of up to 25 days postbilateral occlusion (n=approximately 9/time point). Collateral blood flow to the calf muscles, determined with microspheres, increased modestly over the first few days to approximately 40 ml.min(-1).100 g(-1) in sedentary animals; the increase continued over time to approximately 80 ml.min(-1).100 g(-1) in the trained animals. Diameters of the isolated collateral vessels increased progressively over time, whereas an increased vessel compliance observed at low pressures was similar across time. These responses were greater in the trained animals. The time course of upregulation of vascular endothelial growth factor and placental growth factor, and particularly endothelial nitric oxide synthase and fms-like tyrosine kinase 1, mRNAs in the isolated collateral vessel implicates these factors as integral to the arteriogenic process. Collateral vessel enlargement and increased compliance at low pressures contribute to the enlarged circuit available for collateral blood flow. However, modulation of the functioning collateral vessel diameter, by smooth muscle tone, must occur to account for the observed increases in collateral blood flow measured in vivo.

Exercise-induced vascular remodeling.

Exercise produces a powerful angiogenic stimulus within the active muscle that leads to a functionally important increase in capillarity. Further, exercise can increase flow capacity by enlarging the caliber of arterial supply vessels. These adaptations are achieved by the processes of angiogenesis and arteriogenesis, respectively.

Angiogenic growth factor expression in rat skeletal muscle in response to exercise training.

Angiogenesis occurs in skeletal muscle in response to exercise training. To gain insight into the regulation of this process, we evaluated the mRNA expression of factors implicated in angiogenesis over the course of a training program. We studied sedentary control (n = 17) rats and both sedentary (n = 18) and exercise-trained (n = 48) rats with bilateral femoral artery ligation. Training consisted of treadmill exercise (4 times/day, 1-24 days). Basal mRNA expression in sedentary control muscle was inversely related to muscle vascularity. Angiogenesis was histologically evident in trained white gastrocnemius muscle by day 12. Training produced initial three- to sixfold increases in VEGF, VEGF receptors (KDR and Flt), the angiopoietin receptor (Tie-2), and endothelial nitric oxide synthase mRNA, which dissipated before the increase in capillarity, and a substantial (30- to 50-fold) but transient upregulation of monocyte chemoattractant protein 1 mRNA. These results emphasize the importance of early events in regulating angiogenesis. However, we observed a sustained elevation of the angiopoietin 2-to-angiopoietin 1 ratio, suggesting continued vascular destabilization. The response to exercise was (in general) tempered in high-oxidative muscles. These findings place importance on cellular events coupled to the onset of angiogenesis.

Vastus lateralis fatigue alters recruitment of musculus quadriceps femoris in humans.

This study tested the hypothesis that fatigue of a single member of musculus quadriceps femoris (QF) would alter use of the other three muscles during knee extension exercise (KEE). Six men performed KEE with the left QF at a load equal to 50% of the 4 x 10 repetitions maximum. Subsequently, electromyostimulation (EMS), intended to stimulate and fatigue the left m. vastus lateralis (VL), was applied for 30 min. Immediately after EMS, subjects repeated the KEE. Transverse relaxation time (T2)-weighted magnetic resonance images were taken before and after each bout of KEE and at 3 and 30 min of EMS to assess use and stimulation, respectively, of the QF. T2 of each of the QF muscles was increased 8-13% after the first KEE. During EMS, T2 increased (P < 0.05) even more in VL (10%), whereas it decreased (P < 0.05) to pre-KEE levels in m. vastus medials (VM) and m. rectus femoris (RF). The VL and, to some extent, the m. vastus intermedius were stimulated, whereas the VM and RF were not, thereby recovering from the first bout of KEE. Isometric torque, initially 30% of maximal voluntary, was reduced to 13% at 3 min and 7% at 30 min. T2 was greater (P < 0.05) after the second than the first bout of KEE, especially the increase for the VM and RF. These results suggest that subjects were able to perform the second bout with little contribution of the VL by greater use of the other QF muscles. The simplest explanation is increased central command to the QF such that the intended act could be accomplished despite acute fatigue of one of its synergists.