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Departments of Veterinary Biomedical Sciences and Physiology and Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri 65211
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We tested the hypothesis that aging
decreases endothelium-dependent vasodilation in feed arteries perfusing
rat skeletal muscle. In addition, we tested the hypothesis that
attenuated vasodilator responses are associated with decreased
endothelial nitric oxide synthase (eNOS) and superoxide dismutase-1
(SOD-1) expression. Soleus feed arteries (SFA) and gastrocnemius feed
arteries (GFA) were isolated from young (4 mo) and old (24 mo) male
Fischer 344 rats. Feed arteries from the right hindlimb were cannulated
with two glass micropipettes for examination of endothelium-dependent [acetylcholine (ACh)] and endothelium-independent [adenosine
(Ado) or sodium nitroprusside (SNP)] vasodilator function. Feed
arteries from the left hindlimb were frozen and used to assess eNOS and SOD-1 protein and mRNA expression. In SFA, endothelium-dependent dilation to ACh was reduced in old rats (0.9 ± 0.04 vs. 0.8 ± 0.03), whereas dilator responses to Ado and SNP were similar in SFA
of young and old rats. In GFA, vasodilator responses to ACh, Ado, and SNP were not altered by age. eNOS and SOD-1 protein expression declined with age in SFA (
71 and 54%, respectively) but not in
GFA. eNOS and SOD-1 mRNA expression were not altered by age in SFA or
GFA. Collectively, these data indicate aging induces muscle-specific
impairment of endothelium-dependent vascular function in SFA.
endothelial nitric oxide synthase; superoxide dismutase; nitric oxide; acetylcholine; sodium nitroprusside
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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RESULTS FROM SEVERAL STUDIES indicate that endothelial function in conduit arteries declines with age in humans and animals (3, 4, 7, 8, 10, 11, 16, 23). The endothelial dysfunction induced by aging is characterized by blunted vasodilator responses of conduit arteries to select endothelium-dependent agonists (3, 4, 7, 8, 10, 11, 16, 23). The mechanism(s) for the detrimental effects of age on endothelium-dependent dilation is not fully understood; however, age-associated decrements in the ability of endothelial cells to produce and/or release nitric oxide (NO) may contribute to the dysfunction (3, 11, 16). This speculation is supported by experimental evidence indicating that vasodilation in response to ACh and bradykinin is impaired in aorta from senescent subjects, whereas dilation to sodium nitroprusside (SNP) is not compromised (3, 5, 16).
An age-associated decline in the expression of endothelial NO synthase
(eNOS), decreasing local production of NO, is one mechanism that may
contribute to impaired endothelium-mediated dilation in conduit
arteries of senescent animals. Indeed, age-related reductions eNOS mRNA
expression have been reported in aorta of senescent rats (3,
6). Alternatively, decreased expression of Cu/Zn-dependent
superoxide dismutase (SOD-1) may contribute to impaired
endothelium-mediated dilation by compromising the ability to scavenge
superoxide anion (O
Although endothelial dysfunction is well documented in aorta of senescent rats, the effect of age on endothelium-dependent dilation in arteries that perfuse skeletal muscle is not known, and the effect of age on eNOS and SOD-1 expression has not been studied in feed arteries. Consequently, the purpose of this study was to test the hypothesis that aging decreases endothelium-dependent vasodilator responses in skeletal muscle feed arteries. In addition, we tested the hypothesis that attenuated vasodilator responses are associated with decreased eNOS and SOD-1 expression. Feed arteries from the soleus muscle (SFA) and gastrocnemius muscle (GFA) were studied because of their importance in regulating skeletal muscle blood flow during exercise (25). In addition, previous studies indicate the ability to increase blood flow to the soleus and gastrocnemius muscles during exercise is impaired in senescent rats (13).
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
Before initiation of this study, approval was received from the Institutional Animal Care and Use Committee at the University of Missouri. Male Fischer 344 rats (age 4 and 24 mo; n = 9/age group) were purchased from a commercial dealer (Harlan Sprague Dawley, Indianapolis, IN) and housed in the College of Veterinary Medicine's Animal Care Facility. The facility was maintained at 24°C with a 12:12-h light-dark cycle. Animals were provided food and water ad libitum, and the rats were examined daily by the investigators and by veterinarians affiliated with the University of Missouri's College of Veterinary Medicine.Isolation of Feed Arteries
Rats were anesthetized with an intraperitoneal injection of pentobarbital sodium (50 mg/kg body wt ip). The soleus and gastrocnemius muscles were removed and placed in MOPS-buffered physiological saline solution (PSS) containing (in mM) 145.0 NaCl, 4.7 KCl, 2.0 CaCl2, 1.17 MgSO4, 1.2 NaH2PO4, 5.0 glucose, 2.0 pyruvate, 0.02 EDTA, and 25.0 MOPS, at pH 7.4. Feed arteries from the right leg were dissected and transferred to a Lucite chamber containing MOP-PSS (4°C) for cannulation. Feed arteries from the left leg were placed in ribonuclease-free microcentrifuge tubes and frozen at80°C for
analysis of eNOS and SOD-1 protein and mRNA expression.
Determination of Vasodilator Responses
Preparation of arteries. One end of each feed artery was cannulated with a glass micropipette and secured with 11-0 surgical silk. The opposite end of the feed artery was cannulated with a resistance-matched pipette and secured with 11-0 silk. The micropipettes were attached to separate reservoirs filled with MOPS-PSS supplemented with albumin (1 g/100 ml). The height of each reservoir was initially adjusted to set intraluminal pressure in each feed artery to 60 cmH2O (1 mmHg = 1.36 cmH2O) for 20 min. After 20 min, intraluminal pressure was raised to 90 cmH2O, and the feed arteries were allowed to equilibrate for an additional 40 min at 37°C. At the end of the equilibration period, arteries that did not develop at least 25% spontaneous tone were constricted with phenylephrine. All experimental protocols were subsequently conducted at an intraluminal pressure of 90 cmH2O to approximate in vivo intraluminal pressure (25).
Endothelium-dependent dilation.
Endothelium-dependent dilation was assessed in feed arteries by
adding increasing doses of ACh to the bath solution in cumulative doses
over the range of 10
9 to 104 M in whole-log increments.
Endothelium-independent dilation.
Endothelium-independent dilation was assessed in feed arteries by
adding increasing doses of adenosine (Ado) or SNP to the bath solution
in cumulative doses over the range of 109 to
104 M in whole-log increments. SNP was utilized to
determine whether aging alters the ability of vascular smooth muscle to
respond to NO.
Passive diameter. At the end of each experiment, the PSS bath solution was replaced with Ca2+-free PSS. Feed arteries were incubated for 30 min to determine passive diameter at an intraluminal pressure of 90 cmH2O.
Solutions and Drugs
All reagents used in dose-response experiments were obtained from Sigma Chemical (St. Louis, MO). Reagents were prepared on the day of the experiment.Quantification of eNOS and SOD-1 Expression
mRNA content. Relative differences in eNOS and SOD-1 mRNA expression in single feed arteries were assessed as described previously (26, 28). Briefly, single feed arteries were homogenized in 50 µl LiCl lysis buffer by vortexing the sample vigorously for 60 s. The sample was subsequently spun briefly in a microcentrifuge, and the process was repeated four to five times until the artery was completely digested. Poly(A)+ RNA was isolated from the crude lysate with paramagnetic oligo(dT) beads (Dynal), and first-strand cDNA synthesis was performed in a 20-µl volume (Superscript Preamplification System, GIBCO-BRL Life Technologies). Nine microliters of cDNA were used in a PCR using previously published primers and cycling conditions for eNOS or SOD-1 (26, 28). The PCR consisted of 25 cycles to ensure that the reaction was within the linear range for the eNOS and SOD-1 primer sets. All data were standardized by coamplifying eNOS or SOD-1 with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and calculating an eNOS-to-GAPDH or SOD-1-to-GAPDH ratio for each feed artery (26). The sequence for the GAPDH primers has been published previously (28).
Protein content. Differences in eNOS and SOD-1 protein expression were assessed in single feed arteries (matched for diameter and length) by using immunoblot analysis as described previously in detail (15, 28). eNOS protein expression was evaluated with a monoclonal antibody (1:1,600; catalog no. N30020, Transduction Laboratories). SOD-1 protein content was assessed with a polyclonal antibody (1:1,600; catalog no. SOD-100, Stressgen). Immunoblots were evaluated by densitometry by using NIH Image software (National Institutes of Health, Bethesda, MD), and data were expressed as densitometric units. GAPDH was used as an internal standard to control for small differences in protein loading. GAPDH protein content was assessed with a monoclonal antibody (1:10,000, catalog no. MAB374, Chemicon).
Statistical Analysis
All values are means ± SE. Between-group differences in body mass, passive diameter, as well as eNOS and SOD-1 mRNA and protein expression were assessed by using Student's t-tests for unpaired observations. Concentration-response curves were expressed as relative diameter and analyzed by two-way ANOVA with repeated measures on one factor (dose). Relative diameter was calculated as Ddose/DP, where Ddose is measured diameter for a given dose (ACh, Ado, or SNP) and DP is maximal passive diameter. When a significant F value was obtained, post hoc analyses were performed with Duncan's multiple-range test. When more than one artery was studied from a single animal, concentration-response data were averaged; therefore, one animal counted as one observation. Statistical significance was set at the P
0.05 probability level.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Characteristics of Rats
Characteristics of the young and old rats are shown in Table 1. The body weight of old rats was significantly greater than young rats. Maximal passive diameter was greater in GFA than in SFA; however, there was not a significant main effect of age in SFA or GFA.
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Vasodilator Responses
Before dose-response curves were initiated, percent tone in SFA and GFA was similar in young and old rats. Repeated-measures ANOVA indicated that ACh elicited a concentration-dependent dilation of feed arteries (Fig. 1) and a significant age × dose interaction (P = 0.004). Post hoc analyses revealed that endothelium-dependent dilation to high doses of ACh was significantly less in SFA from old rats than in SFA from young rats (Fig. 1A). In contrast, ACh-induced dilation was not impaired in GFA from old rats (Fig. 1B).
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Ado elicited a modest, but significant, dose-dependent dilation of SFA
from young (18%) and old (12%) rats (Fig.
2). Similarly, Ado elicited a
dose-dependent dilation of GFA. There was not a significant main effect
of age on Ado-induced dilation in SFA (P = 0.83) or GFA
(P = 0.52) (Fig. 2, A and B).
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SNP elicited a concentration-dependent dilation of SFA and GFA (Fig.
3). There was not a significant main
effect of age on SNP-induced dilation in SFA (P = 0.15)
or GFA (P = 0.42) (Fig. 3, A and
B).
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eNOS Expression
The effect of aging on eNOS protein expression in feed arteries from the soleus and gastrocnemius muscle is shown in Fig. 4. Immunoblot analysis revealed that eNOS protein expression declined with age in SFA (71%) but not in GFA
(Fig. 4, A and B). Semi-quantitative PCR revealed
that eNOS mRNA expression was not altered by age in SFA or GFA (Fig.
5).
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SOD-1 Expression
Immunoblot analysis revealed that SOD-1 protein expression declined with age in SFA (54%) but not in GFA (Fig.
6). SOD-1 mRNA expression was not altered
by age in SFA or GFA (Fig. 7).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The purpose of this study was to test the hypothesis that aging decreases endothelium-dependent vasodilation in skeletal muscle feed arteries and that the attenuated vasodilator responses are associated with decreased expression of eNOS and/or SOD-1. The primary findings of this study were as follows. 1) Endothelium-dependent dilation to ACh was blunted in SFA but not in GFA. 2) Dilation to Ado was not compromised by age in SFA or GFA. 3) Endothelium-independent dilation to SNP was not significantly different in feed arteries from young and old rats. 4) eNOS and SOD-1 protein expression decreased with age in SFA but not in GFA. 5) eNOS and SOD-1 mRNA expression were not altered by age in SFA or GFA. These results suggest that age induces muscle-specific impairment of endothelium-dependent dilation in SFA.
In the present study, vasodilator responses to ACh were blunted in SFA from old rats (Fig. 1). These data are in accord with previous studies indicating that ACh-induced dilation is impaired in aorta from senescent rats (3, 5, 16) and demonstrate that age-associated decrements in endothelial function can occur in skeletal muscle feed arteries. Given that ACh-induced dilation is mediated largely by endothelium-derived NO (14), blunted vasodilator responses to this agonist suggests that the ability of SFA to produce NO is impaired by aging.
In the present study, Ado elicited a modest, but significant, vasodilator response in SFA (Fig. 2). Importantly, the dilator response to Ado was similar in young and old rats. In rats, Ado is a dilator that has been reported to mediate its effects primarily by acting directly on vascular smooth muscle (1). The finding that dilation to Ado was not different in old rats, whereas dilation to the endothelium-dependent agonist (ACh) was impaired, is consistent with our interpretation that aging selectively impairs NO-mediated vasodilator mechanisms.
Importantly, dilation to SNP (a NO donor) was not impaired in SFA from senescent rats. Indeed, the trend was toward enhanced vasodilator responses to exogenous NO in SFA (P = 0.15). Enhanced smooth muscle responses to NO have been reported previously in aortic rings from senescent rats (16) and may represent smooth muscle adaptation to partially compensate for attenuated release of endothelium-derived NO in SFA from senescent rats.
In this study, eNOS protein expression decreased with age in SFA (Fig. 4). These data suggest that decreased eNOS protein expression may contribute to blunted ACh-induced dilation by impairing the ability to produce endothelium-derived NO. Further studies are needed, however, to determine whether age-related reductions in eNOS expression are associated with decrements in NO production in these arteries. The mechanism(s) by which aging decreases eNOS protein expression is not known. One possibility is that age-associated reductions in resting blood flow to the soleus muscle may lead to decreased shear stress on the endothelial lining of SFA. It is well documented that shear stress regulates eNOS expression in vascular endothelial cells (19-22, 24, 27). In addition, previous studies have demonstrated that chronic reductions in soleus muscle blood flow induced by hindlimb unweighting are associated with reductions in eNOS expression and ACh-induced dilation in SFA (15, 18). Although previous studies to determine the effect of aging on skeletal muscle blood flow did not reveal age-related decrements in resting blood flow to the rat hindlimb (9, 13), the effect of aging on intraluminal shear stress within SFA is not known.
Decreased eNOS protein expression may also be mediated by age-associated reductions in physical activity. During exercise, blood flow increases to provide muscle with an adequate supply of oxygen and nutrients. It is well documented that flow/shear stress is an important signal regulating eNOS expression in blood vessels (19, 27). Consequently, age-associated reductions in physical activity and associated increases in blood flow may remove an important signal for the maintenance of eNOS expression. In addition, decreased physical activity may reduce the frequency and intensity of soleus muscle contraction. Awolesi and associates (2) reported previously that eNOS expression can be regulated by cyclic strain in endothelial cells; therefore, it is conceivable that decreased muscular activity associated with advancing age may contribute to decreased eNOS expression in SFA.
Interestingly, eNOS mRNA expression was similar in SFA from young and old rats (Fig. 5). These data are contrary to our hypothesis and suggest the possibility that age-associated reductions in eNOS protein expression may involve a decreased rate of protein synthesis and/or increased rate of protein degradation rather than changes in eNOS gene expression. Alternatively, decreased eNOS mRNA expression may have occurred at an earlier age, initiating the changes in eNOS protein expression observed in the 24-mo-old rats.
An additional finding of this study was that aging was associated with
decreased SOD-1 protein expression in SFA (Fig. 6). Age-related
reductions in SOD-1 protein expression may contribute to impaired
ACh-induced dilation of SFA by impairing the ability to scavenge
O
Interestingly, age-associated reductions in ACh-induced dilation did not occur in GFA (Fig. 1). Nor were there age-associated reductions in eNOS or SOD-1 protein expression. The mechanism by which aging induces muscle-specific impairment of endothelium-dependent dilation is not known but may involve differences in muscle fiber type and/or fiber recruitment patterns. The soleus muscle is a slow oxidative skeletal muscle that is recruited at rest and has relatively high resting blood flow (17). By comparison, the gastrocnemius muscle is composed of a mixture of slow oxidative, fast oxidative glycolytic, and fast glycolytic fibers (17). Consequently, this muscle is less active under resting conditions and has relatively lower blood flow under resting conditions (17). It is conceivable, therefore, that age-associated reductions in physical activity selectively reduce blood flow/shear stress or the frequency and intensity of contraction in the soleus muscle.
In summary, the results of this study indicate that aging induces
impairment of endothelium-dependent dilation in SFA but not in GFA. The
age-induced change in endothelial function in SFA is characterized by
attenuated vasodilator responses to ACh but not to Ado. In addition,
the ability of vascular smooth muscle to respond to SNP was not
impaired by aging. Collectively, these findings suggest
endothelium-dependent vasodilator mechanisms are impaired in SFA from
senescent rats. Age-associated reductions in eNOS protein expression in
SFA may contribute to blunted endothelium-dependent dilation by
decreasing NO production. Decreased SOD-1 protein expression may
contribute to attenuated NO-mediated dilation by decreasing the ability
to scavenge O
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ACKNOWLEDGEMENTS |
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The authors gratefully acknowledge the expert technical assistance of Pam Thorne and Tammy Strawn.
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FOOTNOTES |
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This work was supported by National Institute on Aging Grant AG-00988 (to C. R. Woodman) and National Heart, Lung, and Blood Institute Grant HL-36088 (to M. H. Laughlin).
Address for reprint requests and other correspondence: C. R. Woodman, Dept. of Veterinary Biomedical Sciences W108 Veterinary Medicine, 1600 E. Rollins Rd., Univ. of Missouri, Columbia, MO 65211 (E-mail: woodmanc{at}missouri.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/japplphysiol.00461.2002
Received 24 May 2002; accepted in final form 19 July 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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 R. D. Shipley and J. M. Muller-Delp Aging decreases vasoconstrictor responses of coronary resistance arterioles through endothelium-dependent mechanisms Cardiovasc Res, May 1, 2005; 66(2): 374 - 383. [Abstract] [Full Text] [PDF]
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C. R. Woodman, E. M. Price, and M. H. Laughlin Shear stress induces eNOS mRNA expression and improves endothelium-dependent dilation in senescent soleus muscle feed arteries J Appl Physiol, March 1, 2005; 98(3): 940 - 946. [Abstract] [Full Text] [PDF]
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D. N. Proctor, K. U. Le, and S. J. Ridout Age and regional specificity of peak limb vascular conductance in men J Appl Physiol, January 1, 2005; 98(1): 193 - 202. [Abstract] [Full Text] [PDF]
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J. C. Sullivan, E. D. Loomis, M. Collins, J. D. Imig, E. W. Inscho, and J. S. Pollock Age-related alterations in NOS and oxidative stress in mesenteric arteries from male and female rats J Appl Physiol, October 1, 2004; 97(4): 1268 - 1274. [Abstract] [Full Text] [PDF]
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D. Sun, A. Huang, E. H. Yan, Z. Wu, C. Yan, P. M. Kaminski, T. D. Oury, M. S. Wolin, and G. Kaley Reduced release of nitric oxide to shear stress in mesenteric arteries of aged rats Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2249 - H2256. [Abstract] [Full Text] [PDF]
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S. A. Spier, 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., May 1, 2004; 556(3): 947 - 958. [Abstract] [Full Text] [PDF]
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C. R. Woodman, E. M. Price, and M. H. Laughlin Selected Contribution: Aging impairs nitric oxide and prostacyclin mediation of endothelium-dependent dilation in soleus feed arteries J Appl Physiol, November 1, 2003; 95(5): 2164 - 2170. [Abstract] [Full Text] [PDF]
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