Endurance exercise training elicits a number of physiological adaptations, including increased maximal oxygen consumption (V̇O2max), increased cardiac output, and increased maximal oxygen extraction (29). Furthermore, training produces an increase in maximal skeletal muscle blood flow capacity in dogs, rats, and humans (29), increases skeletal muscle blood flow during high-intensity exercise in dogs (41), rats (29), and humans (29), but does not appear to alter total skeletal muscle blood flow under resting conditions or during submaximal exercise at similar absolute exercise intensities (29). However, despite similar total blood flow to skeletal muscle, the distribution of blood flow between different muscles and within specific regions of muscle during moderate intensity exercise is altered by training (1). Specifically, blood flow to regions composed primarily of highly oxidative muscle fibers is increased while blood flow to primarily glycolytic regions of muscle is reduced and flow to nonlocomotory muscle is not altered (41). Thus, exercise training causes blood flow (and oxygen delivery) to be increased to the fibers whose adenosine triphosphate (ATP) generation is most dependent on oxygen and decreased to fibers that are less dependent on oxygen availability for ATP production.
One mechanism by which endurance exercise training may alter blood flow is by changing either endothelial or smooth muscle control of vascular resistance. Furchgott and Zawadski (10) discovered more than two decades ago that the endothelium is an important regulator of vascular tone, and there has been much interest in the subject in years since. The endothelium is located in a strategic position, between the blood and the vascular smooth muscle, and it responds to changes in shear stress and a host of chemical signals by producing factors (nitric oxide (NO), prostacyclin (PGI2), and/or one or more endothelium-derived hyperpolarizing factors (EDHF)) that act on the vascular smooth muscle to regulate vascular tone (29). Exercise training-induced alterations in any of these signaling pathways would lead to changes in endothelial control of blood flow.
Cross-sectional and longitudinal studies in human subjects have found that exercise training improves endothelial function more consistently in subjects who had blunted endothelial function prior to training than in normal subjects (12). These conclusions, combined with our experience with similar studies in animals, stimulated the question: does the current literature indicate a similar interactive effect of endothelial health and exercise in animals such that exercise training has a greater effect on endothelial function in conditions of abnormal endothelial function? Therefore, this review has three purposes: 1) to evaluate the hypothesis that endurance exercise training enhances endothelial function in normal health and preserves or restores endothelial function in animal models of disease with endothelial dysfunction, 2) to compare the effects of short-term (1-4 wk) training versus long-term training on endothelial function in animal models, and 3) to evaluate the hypothesis that endurance exercise training has a generalized, systemic effect such that it improves endothelial function both in vascular beds that experience increased metabolism, blood flow, and/or vascular wall shear stress during exercise bouts and in vascular beds in which metabolism, blood flow, and/or vascular wall shear stress are not increased during bouts of exercise. It should be noted that this review specifically examines the adaptations to endurance exercise training rather than resistance exercise training.
ENDOTHELIAL ADAPTATIONS TO TRAINING IN NORMAL (YOUNG) HEALTHY ANIMALS
The most common measure of endothelial function/health is a measurement of endothelium-dependent dilation/relaxation (EDD). In 1993, Delp et al. (8) reported that relaxation to acetylcholine (ACh), an endothelium-dependent dilator, was enhanced by 12 wk of exercise training. l-NAME, an arginine analog that competitively inhibits NO production, partially inhibited EDD in aortic rings from both sedentary and trained rats, but the inhibition was greater in rings from trained rats such that L-NAME abolished the difference between groups. Exercise training also caused an increase in endothelial cell α2-mediated dilation. Training-induced alterations appeared to be specific to the aortic endothelium since endothelium-independent dilations (to sodium nitroprusside) were not altered by training.
Examination of the time course of training-induced increases in aortic EDD revealed no change following a single exercise bout or after training durations of <4 wk, but aortic EDD was increased following training programs of 4 and 10 wk (7). Subsequent studies using 8-10 wk of training in rats (5,6,63) confirmed these results (Table 1). Also, 16-19 wk of training in pigs (47) produce changes in aortic endothelial gene expression consistent with enhanced EDD following long-term training.
The effect of exercise training on EDD in other conduit arteries differs from the aorta (Table 2). Results of a study examining porcine femoral and brachial arteries indicate that short-term training (7 d) elicits enhanced EDD in the brachial but not the femoral artery (37). Relaxations to sodium nitroprusside (endothelium independent) were not altered. In contrast, long-term training of pigs (16-20 wk) had no effect on EDD in either the brachial or femoral arteries of male pigs (32). In female pigs, femoral artery responses were not altered with short- or long-term training (32,36), but EDD was improved in brachial arteries of female pigs trained for 20 wk (32). Thus, results do not consistently reveal enhanced EDD of arteries providing blood to limb muscles of trained pigs. Indeed, in normal male and female pigs, exercise training has only moderate effects on EDD in conduit arteries, as the amount of increase in EDD is modest in normal female pigs even when statistically significantly increased. Finally, EDD in porcine renal, mesenteric, and hepatic arteries (36) and in porcine pulmonary arteries (22) is not altered by 16-20 wk of exercise training. These data indicate that long-term exercise training does not increase EDD throughout the porcine arterial tree, that is, training does not have a generalized effect on endothelial function in conduit arteries of nonmuscular vascular beds.
Skeletal muscle resistance vessels.
Short-term training consistently causes endothelial adaptations in skeletal muscle resistance vessels (Table 3). Three to 4 wk of daily exercise in rats increased EDD of gracilis muscle arterioles to ACh and L-arginine (53) and to increased levels of perfusate flow (27). The augmented response to flow was partially abolished by blocking eNOS or cyclooxygenase, indicating that both NO and PGI2 pathways were enhanced (27). Flow-induced dilation of arterioles from the plantaris muscle was also increased in rats by 3-4 wk of exercise (51). Thus, available evidence indicates that short-term exercise training increases EDD in resistance arteries of rat skeletal muscle.
There have been only a few studies of the effects of long-term training on EDD in skeletal muscle resistance arteries ( Table 3), and results are variable. For example, Lash and Bohlen (28) reported that 8 wk of exercise training did not alter EDD in spinotrapezius muscle arteries of rats, but 16 wk of training did elicit an increased dilation to ACh in first- and second-order arterioles from this muscle. However, they also reported an increased dilation to sodium nitroprusside in first-order arterioles and feed arteries after 16 wk, so it is difficult to know whether the increased dilation in first-order branches was due to adaptations in the smooth muscle alone or whether the endothelium also contributed. It should be noted that functional dilation (response to electrical stimulation) was increased at 8 wk, but this augmentation was almost gone by 16 wk of training. Thus the time course of adaptations in EDD was dissociated from the time course of adaptations in functional dilation. Although the oxidative capacity of the spinotrapezius (as measured by citrate synthase activity) was increased a small amount in this study, it should be noted that the spinotrapezius is not a primary locomotory muscle.
The soleus muscle is used extensively in posture maintenance and locomotion and is a muscle whose blood flow is increased during exercise (1). Exercise training for 12 wk did not alter EDD in rat soleus muscle feed arteries (19). This observation may be the result of the fact that the soleus muscle is used constantly in the maintenance of posture in the standing rat. Due to this high level of recruitment, soleus muscle metabolic activity is high, even in sedentary rats, as is the blood flow and shear stress through the soleus muscle feed arteries (18). Consistent with this interpretation are results of a study in which decreasing metabolic activity and blood flow of the soleus muscle via hindlimb unweighting produced a reduction in EDD (20). The conclusion of studies altering soleus activity with chronic training and chronic inactivity indicate that EDD in soleus feed arteries can be reduced, but not enhanced, by chronic alterations in soleus muscle activity. This is probably the result of the high level of metabolism and blood flow to the soleus during normal daily activity in the rat, which is sufficient to maintain EDD near optimal levels, even in untrained rats.
Another study examining long-term training used a high-intensity sprint training protocol for 10 wk in rats (33). Sprint training increased the hindlimb response to ACh and increased EDD in second-order arterioles of the white portion of the gastrocnemius, but not in gastrocnemius feed arteries, second-order arterioles from the red region of gastrocnemius, or third-order arterioles from the white portion. In contrast, McAllister et al. (35) found that moderate-intensity training for 8-12 wk resulted in enhanced EDD and increased endothelial NOS levels in arterioles from the red, but not white portion of gastrocnemius. Together with the data from Lash and Bohlen (28) described above, these data indicate that the pattern of skeletal muscle resistance artery endothelial adaptation to exercise training is very complex, and much work still needs to be done in order to define the manner in which these adaptations occur in the skeletal muscle arteriolar network.
Coronary vascular bed.
In larger arteries of the heart, short-term exercise training consistently increases EDD (Table 2). Studies in dogs (49) and pigs (31) report increased EDD following 7-10 d of daily exercise. Furthermore, 10 d of training in dogs increases NO production and eNOS expression in large coronary arteries (56). Interestingly, 7 d of training did not alter EDD in porcine resistance arterioles (31), indicating that endothelial adaptations appear to be limited to larger coronary vessels when the training program is of short duration. In contrast, adaptations to longer term exercise training are not observed in larger coronary arteries and appear to be limited to smaller resistance vessels. Oltman et al. (44) found that 13-20 wk of training had no effect on EDD in porcine coronary arteries. However, when porcine resistance arterioles were studied, 16-20 wk of training resulted in an enhancement of EDD (40). Thus, it appears that the smaller coronary resistance arterioles have enhanced EDD after a long-term training protocol, but EDD is enhanced in the larger coronary conduit arteries only after short-term training.
Vascular beds in noncontracting tissue.
It has been proposed that there would be no training-induced adaptation in arteries of tissues that do not increase activity during exercise because these tissues have neither increased metabolism nor increased blood flow (34). Additionally, alterations in blood flow have been shown to be greatest in the specific muscle regions that have the greatest relative increase in activity during exercise training bouts (29). However, there is evidence in humans that leg cycle training (26) or walking (16) can elicit enhanced EDD in the forearm, tissue that would not be active during the training bouts. These data suggest that in healthy humans, regular exercise that uses a large muscle mass (i.e., legs) may bring about systemic adaptations in endothelial function (34).
McAllister et al. (36) examined the responses of the porcine mesenteric, renal, and hepatic conduit arteries of pigs following long-term training and found no endothelial adaptations to exercise in these vessels. As summarized in Table 2, these data indicate that long-term training in pigs does not alter EDD of non-skeletal muscle conduit arteries. Additionally, short term training does not alter flow-induced dilation of rat mesenteric arterioles (51), supporting the notion that vascular endothelium in splanchnic regions does not undergo adaptation to training.
As mentioned above, short-term training has been reported to increase EDD in rat gracilis arterioles ( 27,53) and longer training protocols increase EDD in the rat spinotrapezius muscle (28). This is interesting because neither the gracilis (1) nor spinotrapezius (42) arteries have increased blood flow during exercise. Also, gracilis blood flow during exercise is not altered by training (1). Thus, the fact that EDD is increased by training in these muscles suggests that training can induce adaptations in endothelial function in resistance vessels of skeletal muscle tissue that has little or no increase in activity or blood flow during training bouts. Furthermore, exercise training has been reported to enhance EDD in the rat carotid artery (25), suggesting that conduit arteries from inactive regions can also have training-induced endothelial augmentation. Thus, while generalized adaptations in endothelial function do not occur in the pig model (36) or in the mesenteric circulation of the rat (51), data from other vascular beds of the rat in regions that are inactive during exercise support results from human studies indicating that improved EDD can occur in resistance vessels in nonactive regions of the body and that exercise training has a nonspecific, systemic effect on endothelial function. A potential explanation for improved EDD in arteries of tissue with no change or decreased blood flow during exercise is that vascular wall shear stress may increase in arteries perfusing these regions during exercise even if flow does not increase, due to decreased diameters of these arteries during exercise. During exercise, there is a generalized increase in sympathetic nerve activity that causes vasoconstriction of arteries in many regions of the body. This vasoconstriction serves to shunt blood flow away from nonactive regions toward the active regions that require increased oxygen and substrate delivery. It may be that vasoconstriction in nonactive regions actually increases wall shear stress in the resistance vasculature of some nonactive body regions and that long-term exposure to this stimulus results in enhanced endothelial function in these regions. A second potential explanation is that some chemical mediator of enhanced endothelial function is produced in actively contracting muscle and carried via the vasculature to nonactive regions.
Summary of exercise training in normal, healthy subjects.
In summary, it appears that endurance exercise training has nonuniform effects on arterial endothelium in normal, healthy animals. The effects of training are determined by a number of known parameters including the length of the training protocol, the branch order of the vasculature studied (30), and the specific tissue studied. Current results indicate that long-term endurance exercise training induces enhanced EDD in the aorta and in resistance arteries of the heart. Short-term, but not long-term, training increases EDD in coronary conduit arteries. Short-term training also increases EDD in resistance arterioles of the gracilis and plantaris muscles. However, after long-term training, only modest increases in EDD are reported in the spinotrapezius and no changes are seen in soleus resistance arteries. These findings parallel the human literature in that in normal, healthy individuals, endurance exercise training does not consistently cause increases in endothelial function.
It may seem counterintuitive that short exposure to training causes adaptations in endothelial function while increasing the duration of exposure to the training stimulus causes a regression of these adaptations. It has been proposed that these observations reveal the sequence of adaptations in vascular control and structure throughout a training program (31,34). Increases in vascular wall shear stress produced during exercise hyperemia may be an important stimulus for augmentation of EDD (58) and subsequently for changes in vascular structure (45). According to this hypothesis, short-term exercise training causes increases in shear stress and the result is an increased expression of eNOS and possibly other proteins that help to increase EDD of arteries. As the duration of the training period increases, eNOS, vascular endothelial growth factor (VEGF), and other factors produced during exercise bouts elicit vascular remodeling, formation of new vessels, and enlargement of existing vessels. These structural adaptations return vascular shear stress to normal levels and EDD also returns to normal. In support of this hypothesis, eNOS mRNA levels can be increased in as little as 2-4 h by in vitro increases in flow (58), and increased eNOS protein expression can occur in 7-10 d (56). However, strong evidence regarding the nature and time course of structural adaptations in the arterial microcirculation is not currently available.
ENDOTHELIAL ADAPTATIONS TO TRAINING IN CONDITIONS OF ATTENUATED ENDOTHELIAL FUNCTION
Several studies have reported reduced EDD in both conduit and resistance vessels of older versus younger rats (Table 4). Sun et al. (52) found that gracilis arterioles of older rats had reduced sensitivity to wall shear stress and that an 18- to 20-wk treadmill training program increased sensitivity of these arterioles to shear stress. Responses to ACh were also increased by exercise training in the older rats, while responses to sodium nitroprusside were not altered. Spier et al. (50) compared EDD in first-order arterioles of the soleus muscle (primarily slow-oxidative fibers) and of the white portion of the gastrocnemius muscle (primarily fast, glycolytic fibers). They found that aging reduced EDD to ACh in the arterioles of the soleus, but not the white gastrocnemius muscle, and that 12 wk of low-intensity exercise training increased ACh-induced EDD in soleus arterioles from young and old rats and in white gastrocnemius arterioles from young, but not old, rats. Both aging and exercise training effects were due to differences in NO production, and training was found to increase both eNOS mRNA and eNOS protein levels in arterioles from both muscles in both age groups. Although treadmill running in old rats has been reported to reduce aortic sensitivity to lower doses of ACh (≤10−7 mol·L−1 or less) (15,55), the preponderance of data, particularly in resistance vessels, indicates that exercise training in older subjects reverses the age-related decline in EDD. These data support studies in humans that have also found that training can attenuate the age-related decline in EDD (34,39).
Griffin et al. (13) reported that 16 wk of treadmill running elicited increased EDD in coronary conduit arteries from both the collateral-dependent region and the normal region perfused by the left anterior descending artery (LAD) in a porcine model of chronic coronary occlusion. The enhanced EDD was the result of training-induced increases in production of NO and EDHF. Griffin et al. subsequently reported that coronary arterioles from the collateral-dependent region also exhibited training-induced increases in EDD and increased eNOS mRNA expression (14). Similarly, VEGF-induced EDD of coronary arterioles from the collateral-dependent region is enhanced by exercise training due to increased NO production (9). EDD of the pulmonary arteries from these coronary artery occluded pigs are also enhanced by 16 wk of training (23), an adaptation to training that was not found in normal pigs (22). The increased pulmonary artery EDD appeared to result both from an increase in NO production and reduced production of a vasoconstrictor prostanoid. Thus, in this group of studies using the coronary artery occlusion model, exercise training consistently enhances EDD in coronary and pulmonary arteries (Table 4).
There have also been some studies in which endurance exercise training has been used in models of heart failure. In dogs with congestive heart failure induced by cardiac pacing, exercise training improved EDD (57,64). Wang et al. (57) reported that training preserved EDD of coronary arteries and increased eNOS protein expression. Yi et al. (64) reported that training preserved EDD of the left circumflex coronary artery to arachidonic acid, but that prostacyclin- or nitroglycerin-induced dilations were not altered by training. Thus, training preserved EDD in coronary arteries during the development of heart failure, but did not alter vascular smooth muscle function. These findings are similar to those in humans, in whom a number of studies have also found that coronary artery disease or heart failure causes reduced EDD and that endurance exercise training restores EDD to normal levels (12,34,39). Interestingly, the authors are not aware of any animal studies that have examined the effects of exercise training on EDD in peripheral arteries in heart failure.
A large number of studies have reported reduced EDD in hypercholesterolemia (Table 4) that is reversed or prevented by exercise training of mice (43,46), rabbits (21,61,62), and pigs (54,59,60). In a genetic model of mouse hypercholesterolemia, the apolipoprotein E knockout mouse, EDD of the thoracic aorta was decreased in relation to wild-type mice and exercise training restored normal EDD (43). Expression of eNOS protein in the carotid artery of apolipoprotein E knockout mice was reduced, but was also restored to normal levels by exercise training (46). In rabbit aorta, hypercholesterolemia decreased EDD to ACH, and this was linked to reductions in endothelial production of both NO and EDHF (61,62). Treadmill exercise training increased production of NO and EDHF and restored ACh-induced EDD. At least part of the reduction in endothelial production of NO and EDHF may result from impaired calcium signaling in endothelial cells because hypercholesterolemia decreased the ACh-mediated elevation in endothelial cell calcium levels in rabbit femoral arteries, an alteration that was also reversed by exercise training (21). Finally, data from studies using pigs demonstrate that hypercholesterolemia decreases NO-mediated signaling in coronary and brachial arteries (54,59,60). Exercise training restored EDD of coronary arteries by increasing NO-mediated dilation and decreasing production of a prostanoid vasoconstrictor (59,60). Thus, available results indicate that hypercholesterolemia reduces and exercise training restores NO-mediated EDD. Similar results have been found in a number of human studies (12,34,39).
Studies using rings of aorta (3,4,11), carotid artery (2,4), and/or mesenteric artery (2) to examine the effects of endurance exercise training in spontaneously hypertensive rats (SHR) have consistently shown that EDD is reduced by hypertension and that attenuated NO production is at least partially responsible (Table 4). Exercise training improves EDD in these arteries from SHR, and NO production is increased by training in these arteries (2,4). Additionally, exercise training increases expression of eNOS in SHR, which would explain the findings of increased NO production (11). Graham and Rush (11) also examined levels of superoxide dismutase and catalase, two enzymatic scavengers of oxygen free radicals, and found no difference in trained versus sedentary SHR. Interestingly, levels of the pro-oxidant enzyme, NAD(P)H oxidase, were reduced by exercise training, which may have a beneficial effect on the half-life of NO in the vascular wall. Thus, the improvement in EDD with training of hypertensive animals appears to result from increased NO production and availability and not from improved free radical scavenging by antioxidant enzymes or from increases in other endothelium-derived dilators (2). Studies in humans also indicate that EDD is impaired in hypertension and endurance exercise training improves EDD in these subjects (12,34).
Type 2 diabetes mellitus.
Two studies have examined the effects of exercise training on EDD in type 2 diabetes mellitus. Sakamoto et al. (48) found that diabetes reduced aortic EDD in rats and that exercise training improved EDD. Training also increased insulin sensitivity and reduced plasma levels of glucose and insulin. A subsequent study of diabetic rats by Minami et al. (38) found that thoracic aorta and mesenteric artery rings from diabetic rats had reduced responses to ACh, with endothelial production of both NO and EDHF attenuated. Exercise training increased relaxation to ACh and production of both NO and EDHF was increased.
The evidence reviewed in this paper indicates that the effect of endurance exercise training on EDD in normal animals is dependent on both the location of the arteries and the duration of the training program (Fig. 1). In normal, healthy animals, the aortic endothelium consistently demonstrates increased EDD by the fourth week of training and this enhanced EDD persists throughout longer training protocols. In conduit arteries feeding skeletal muscle or inactive tissue, neither short-term (1-4 wk) nor long-term training consistently elicits increases in EDD, while coronary arteries have increased EDD following short-, but not long-term training. Coronary resistance arteries have increased EDD only after long-term training. Resistance arteries from inactive tissues do not exhibit consistent increases in EDD after either short- or long-term training. In conditions in which EDD is compromised such as aging, heart disease, hypercholesterolemia, type 2 diabetes, and hypertension, results indicate that exercise training consistently preserves EDD at normal levels or restores EDD to normal levels. The general conclusion is that even in cases where training has an effect on EDD in healthy animals, this effect is quite modest compared to the effect of training in various disease models. It should be noted that almost all studies of exercise and endothelial function in pathological conditions have examined conduit arteries, so more work is needed to determine how exercise interacts with various diseases in determining EDD and health. Finally, although some evidence indicates a generalized effect of exercise training in that training can enhance EDD even in regions of the body that are not active during training bouts, other evidence indicates that some endothelial adaptations are specific to certain regions, as not all inactive body regions show this effect. Based on this body of evidence, we conclude that long-term exercise training does not significantly increase endothelial function of arteries in normal animals, but exercise training can prevent or reverse the development of endothelial dysfunction that accompanies some diseases.
1. Armstrong, R. B., and M. H. Laughlin. Exercise blood flow
patterns within and among rat muscles after training. Am. J. Physiol.
2. Arvola, P., X. Wu, M. Kahonen, et al. Exercise enhances vasorelaxation in experimental obesity associated hypertension. Cardiovasc. Res.
3. Chen, H. I., and I. P. Chiang. Chronic exercise decreases adrenergic agonist-induced vasoconstriction in spontaneously hypertensive rats. Am. J. Physiol.
4. Chen, H. I., I. P. Chiang, and C. J. Jen. Exercise training increases acetylcholine-stimulated endothelium
-derived nitric oxide release in spontaneously hypertensive rats. J. Biomed. Sci.
5. Chen, S. J., C. C. Wu, and M. H. Yen. Exercise training activates large-conductance calcium-activated K(+) channels and enhances nitric oxide production in rat mesenteric artery and thoracic aorta. J. Biomed. Sci.
6. Chu, T. F., T. Y. Huang, C. J. Jen, and H. I. Chen. Effects of chronic exercise on calcium signaling in rat vascular endothelium
. Am. J. Physiol.
7. Delp, M. D., and M. H. Laughlin. Time course of enhanced endothelium
-mediated dilation in aorta of trained rats. Med. Sci. Sports Exerc.
8. Delp, M. D., R. M. McAllister, and M. H. Laughlin. Exercise training alters endothelium
-dependent vasoreactivity of rat abdominal aorta. J. Appl. Physiol.
9. Fogarty, J. A., J. M. Muller-Delp, M. D. Delp, M. L. Mattox, M.H. Laughlin, and J. L. Parker. Exercise training enhances vasodilation
responses to vascular endothelial growth factor in porcine coronary arterioles exposed to chronic coronary occlusion. Circulation
10. Furchgott, R. F., and J. V. Zawadski. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature
11. Graham, D. A., and J. W. Rush. Exercise training improves aortic endothelium
-dependent vasorelaxation and determinants of nitric oxide bioavailability in spontaneously hypertensive rats. J. Appl. Physiol.
12. Green, D. J., A. Maiorana, G. O'Driscoll, and R. Taylor. Effect of exercise training on endothelium
-derived nitric oxide function in humans. J. Physiol.
13. Griffin, K. L., M. H. Laughlin, and J. L. Parker. Exercise training improves endothelium
-mediated vasorelaxation after chronic coronary occlusion. J. Appl. Physiol.
14. Griffin, K. L., C. R. Woodman, E. M. Price, M. H. Laughlin, and J. L. Parker. Endothelium
-mediated relaxation of porcine collateral-dependent arterioles is improved by exercise training. Circulation
15. Hashimoto, M. Effects of exercise on plasma lipoprotein levels and endothelium
-dependent vasodilatation in young and old rats. Eur. J. Appl. Physiol. Occup. Physiol.
16. Higashi, Y., S. Sasaki, S. A. Kurisu, et al. Regular aerobic exercise augments endothelium
-dependent vascular relaxation in normotensive as well as hypertensive subjects: role of endothelium
-derived nitric oxide. Circulation
17. Indolfi, C., D. Torella, C. Coppola, et al. Physical training increases eNOS vascular expression and activity and reduces restenosis after balloon angioplasty or arterial stenting in rats. Circ. Res.
18. Jasperse, J. L., and M. H. Laughlin. Flow-induced dilation of rat soleus feed arteries
. Am. J. Physiol
19. Jasperse, J. L., and M. H. Laughlin. Vasomotor responses of soleus feed arteries
from sedentary and exercise-trained rats. J. Appl. Physiol.
20. Jasperse, J. L., C. R. Woodman, E. M. Price, E. M. Hasser, and M. H. Laughlin. Hindlimb unweighting decreases ecNOS gene expression and endothelium
-dependent dilation in rat soleus feed arteries
. J. Appl. Physiol.
21. Jen, C. J., H. P. Chan, and H. I. Chen. Chronic exercise improves endothelial calcium signaling and vasodilatation in hypercholesterolemic rabbit femoral artery. Arterioscler. Thromb. Vasc. Biol
22. Johnson, L. R., and M. H. Laughlin. Chronic exercise training does not alter pulmonary vasorelaxation in normal pigs. J. Appl. Physiol.
23. Johnson, L. R., J. L. Parker, and M. H. Laughlin. Chronic exercise training improves ACh-induced vasorelaxation in pulmonary arteries
of pigs. J. Appl. Physiol.
24. Johnson, L. R., J. W. Rush, J. R. Turk, E. M. Price, and M. H. Laughlin. Short-term exercise training increases ACh-induced relaxation and eNOS protein in porcine pulmonary arteries
. J. Appl. Physiol.
25. Kemi, O. J., P. M. Haram, U. Wisloff, and O. Ellingsen. Aerobic fitness is associated with cardiomyocyte contractile capacity and endothelial function in exercise training and detraining. Circulation
26. Kingwell, B. A., B. Sherrard, G. L. Jennings, and A. M. Dart. Four weeks of cycle training increases basal production of nitric oxide from the forearm. Am. J. Physiol.
27. Koller, A., A. Huang, D. Sun, and G. Kaley. Exercise training augments flow-dependent dilation in rat skeletal muscle
arterioles. Role of endothelial nitric oxide and prostaglandins. Circ. Res.
28. Lash, J. M., and H. G. Bohlen. Time- and order-dependent changes in functional and NO-mediated dilation during exercise training. J. Appl. Physiol.
29. Laughlin, M. H., R. J. Korthuis, D. J. Duncker, and R. J. Bache. Control of blood flow
to cardiac and skeletal muscle
. In: Handbook of Physiology: Exercise: Regulation and Integration of Multiple Systems
, L. B. Rowell and J. T. Shepherd (Eds.). New York: Oxford University Press, 1996, p. 705.
30. Laughlin, M. H., J. S. Pollock, J. F. Amann, M. L. Hollis, C. R. Woodman, and E. M. Price. Training induces nonuniform increases in eNOS content along the coronary arterial tree. J. Appl. Physiol.
31. Laughlin, M. H., L. J. Rubin, J. W. Rush, E. M. Price, W. G. Schrage, and C. R. Woodman. Short-term training enhances endothelium
-dependent dilation of coronary arteries
, not arterioles. J. Appl. Physiol.
32. Laughlin, M. H., W. G. Schrage, R. M. McAllister, H. A. Garverick, and A. W. Jones. Interaction of gender and exercise training: vasomotor reactivity of porcine skeletal muscle arteries
. J. Appl. Physiol.
33. Laughlin, M. H., C. R. Woodman, W. G. Schrage, D. Gute, and E. M. Price. Interval sprint training enhances endothelial function and eNOS content in some arteries
that perfuse white gastrocnemius muscle. J. Appl. Physiol.
34. Maiorana, A., G. O'Driscoll, R. Taylor, and D. Green. Exercise and the nitric oxide vasodilator system. Sports Med.
35. McAllister, R. M., J. L. Jasperse, and M. H. Laughlin. Nonuniform effects of endurance exercise training on vasodilation
in rat skeletal muscle
. J. Appl. Physiol.
36. McAllister, R. M., J. K. Kimani, J. L. Webster, J. L. Parker, and M. H. Laughlin. Effects of exercise training on responses of peripheral and visceral arteries
in swine. J. Appl. Physiol.
37. McAllister, R. M., and M. H. Laughlin. Short-term exercise training alters responses of porcine femoral and brachial arteries
. J. Appl. Physiol.
38. Minami, A., N. Ishimura, N. Harada, S. Sakamoto, Y. Niwa, and Y. Nakaya. Exercise training improves acetylcholine-induced endothelium
-dependent hyperpolarization in type 2 diabetic rats, Otsuka Long-Evans Tokushima fatty rats. Atherosclerosis
39. Moyna, N. M., and P. D. Thompson. The effect of physical activity on endothelial function in man. Acta Physiol. Scand.
40. Muller, J. M., P. R. Myers, and M. H. Laughlin. Vasodilator responses of coronary resistance arteries
of exercise-trained pigs. Circulation
41. Musch, T. I., G. C. Haidet, G. A. Ordway, J. C. Longhurst, and J. H. Mitchell. Training effects on regional blood flow
response to maximal exercise in foxhounds. J. Appl. Physiol.
42. Musch, T. I., and D. C. Poole. Blood flow
response to running in the rat spinotrapezius muscle. Am. J. Physiol.
43. Niebauer, J., A. J. Maxwell, P. S. Lin, et al. Impaired aerobic capacity in hypercholesterolemic mice: partial reversal by exercise training. Am. J. Physiol.
44. Oltman, C. L., J. L. Parker, and M. H. Laughlin. Endothelium
of proximal coronary arteries
from exercise-trained pigs. J. Appl. Physiol.
45. Prior, B. M., P. G. Lloyd, H. T. Yang, and R. L. Terjung. Exercise-induced vascular remodeling. Exerc. Sport Sci. Rev.
46. Pynn, M., K. Schafer, S. Konstantinides, and M. Halle. Exercise training reduces neointimal growth and stabilizes vascular lesions developing after injury in apolipoprotein e-deficient mice. Circulation
47. Rush, J. W., J. R. Turk, and M. H. Laughlin. Exercise training regulates SOD-1 and oxidative stress in porcine aortic endothelium
. Am. J. Physiol. Heart Circ. Physiol.
48. Sakamoto, S., K. Minami, Y. Niwa, et al. Effect of exercise training and food restriction on endothelium
-dependent relaxation in the Otsuka Long-Evans Tokushima fatty fat, a model of spontaneous NIDDM. Diabetes
49. Sessa, W. C., K. Pritchard, N. Sedayi, J. Wang, and T. H. Hintze. Chronic exercise in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression. Circ. Res.
50. Spier, S. A., M. D. Delp, C. J. Meininger, A. J. Donato, M. W. Ramsey, and J. M. Muller-Delp. Effects of ageing and exercise training on endothelium
-dependent vasodilatation and structure of rat skeletal muscle
arterioles. J. Physiol.
51. Sun, D., A. Huang, A. Koller, and G. Kaley. Adaptation of flow-induced dilation of arterioles to daily exercise. Microvasc. Res.
52. Sun, D., A. Huang, A. Koller, and G. Kaley. Decreased arteriolar sensitivity to shear stress in adult rats is reversed by chronic exercise activity. Microcirculation
53. Sun, D., A. Huang, A. Koller, and G. Kaley. Short-term daily exercise activity enhances endothelial NO synthesis in skeletal muscle
arterioles of rats. J. Appl. Physiol.
54. Thompson, M. A., K. K. Henderson, C. R. Woodman, et al. Exercise preserves endothelium
-dependent relaxation in coronary arteries
of hypercholesterolemic male pigs. J. Appl. Physiol.
55. Tsutsumi, K., M. Kusunoki, T. Hara, et al. Exercise improved accumulation of visceral fat and simultaneously impaired endothelium
-dependent relaxation in old rats. Biol. Pharm. Bull.
56. Wang, J., M. S. Wolin, and T. H. Hintze. Chronic exercise enhances endothelium
-mediated dilation of epicardial coronary artery in conscious dogs. Circ. Res.
57. Wang, J., G. H. Yi, M. Knecht, B. L. Cai, S. Poposkis, M. Packer, and D. Burkhoff. Physical training alters the pathogenesis of pacing-induced heart failure through endothelium
-mediated mechanisms in awake dogs. Circulation
58. Woodman, C. R., J. M. Muller, J. W. Rush, M. H. Laughlin, and E. M. Price. Flow regulation of ecNOS and Cu/Zn SOD mRNA expression in porcine coronary arterioles. Am. J. Physiol.
59. Woodman, C. R., J. R. Turk, J. W. Rush, and M. H. Laughlin. Exercise attenuates the effects of hypercholesterolemia on endothelium
-dependent relaxation in coronary arteries
from adult female pigs. J. Appl. Physiol.
60. Woodman, C. R., J. R. Turk, D. P. Williams, and M. H. Laughlin. Exercise training preserves endothelium
-dependent relaxation in brachial arteries
from hyperlipidemic pigs. J. Appl. Physiol.
61. Yang, A. L., and H. I. Chen. Chronic exercise reduces adhesion molecules/iNOS expression and partially reverses vascular responsiveness in hypercholesterolemic rabbit aortae. Atherosclerosis
62. Yang, A. L., C. J. Jen, and H. I. Chen. Effects of high-cholesterol diet and parallel exercise training on the vascular function of rabbit aortas: a time course study. J. Appl. Physiol.
63. Yang, A. L., S. J. Tsai, M. J. Jiang, C. J. Jen, and H. I. Chen. Chronic exercise increases both inducible and endothelial nitric oxide synthase gene expression in endothelial cells of rat aorta. J. Biomed. Sci.
64. Yi, G. H., D. Zwas, and J. Wang. Chronic exercise training preserves prostaglandin-induced dilation of epicardial coronary artery during development of heart failure in awake dogs. Prostaglandins Other Lipid Mediat.