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1Department of Physiology, New York Medical College, Valhalla, New York 10595; and 2Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261
Submitted 8 September 2003 ; accepted in final form 27 January 2004
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ABSTRACT |
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endothelium; superoxide; superoxide dismutase
One of the broadly accepted theories of endothelial dysfunction in aging is the increase in oxidative stress. In clinical studies, administration of the antioxidant vitamin C improved vasodilatation to ACh and restored the inhibition by N
-monomethyl-L-arginine, an inhibitor of NO synthase (NOS), of vasodilator responses, indicating that a decreased bioavailability of NO because of the presence of superoxide (O2–·) contributes to endothelial dysfunction in aging (33). Indeed, the production of O2–· within the vascular wall increases with age (7, 13). Also, O2–· formation can be further augmented, resulting in impaired endothelium-dependent dilator responses, by a reduction of superoxide dismutase (SOD) activity (10). Decline in the expression of Cu/Zn-dependent SOD was reported in arteries of skeletal muscle (35) but not in coronary vessels (7) of aged rats. On the other hand, much less is known about changes in SOD activity in vascular aging. We reported previously that scavenging O2–· only partially restored flow-induced dilation in aged vessels (7), suggesting that additional mechanisms, besides the metabolism of NO by O2–·, may also play roles in the development of endothelial dysfunction. Vascular aging is, according to some studies, also characterized by a decrease in the expression of endothelial NOS (eNOS) in small arteries (7, 35) and an increase in large conduit vessels (5, 34). Nevertheless, both the activity of eNOS and the release of NO have been suggested to be reduced in aging (1, 5, 34). Accordingly, an increase in the production of O2–·, a decrease in the activity of SOD, or a decrease in the activation of eNOS could all reduce endothelium-dependent, NO-mediated vasodilatation. However, the underlying mechanisms responsible for the changes in shear stress-activated release of NO in aging have not yet been elucidated.
The aims of the present study were, therefore, to investigate the changes in flow-induced dilation and the release of NO in response to different levels of shear stress in isolated mesenteric arteries of young and aged rats and to explore the possible mechanisms leading to endothelial dysfunction, focusing mainly on the changes in O2–· formation, and eNOS and SOD protein expression and activity.
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METHODS |
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Flow-induced dilation.
To avoid variation in the level of stimulation by shear stress when intraluminal flow was applied to vessels with different internal diameters, as in vessels of 6- and 24-mo-old rats, an initial shear stress (
) of 15 dyn/cm2 [ = 4Q
/
r3; where Q is intraluminal flow, is the viscosity of perfusate (
0.007 P, at 37°C), and r is the radius of the vessel] was applied to all vessels to induce a flow-induced dilation. This was obtained by applying an intraluminal flow calculated according to the basal diameter (the diameter obtained before application of shear stress) of the vessels. Flow was established by a syringe pump (model 100, KD Scientific) coupled with an inflow pressure transducer. An outflow pressure-servo controller maintained constant intravascular pressure at 80 mmHg. During intraluminal flow, intravascular pressure was maintained by lowering outflow pressure to an amount equal to the increase in inflow pressure. A period of 3–5 min of intraluminal flow was applied to obtain a stable dilation. Dilator function of a vessel in response to stimulation by flow was then evaluated by comparing the reduction of shear stress from its initial level, calculated according to the intraluminal flow and the vessel diameter after flow-induced dilation.
Application of shear stress and measurement of perfusate nitrite and nitrate. It has been shown previously that first-order mesenteric arteries of rats exhibit little myogenic constriction at 80 mmHg of intravascular pressure (32). To ensure that the diameter of the vessels is maintained constant at their maximal diameter, adenosine (10–5 M) was added to the suffusion solution. The average diameter of the vessels (334 and 400 µm at 6 and 24 mo, respectively) was calculated by measuring the diameters along the entire length of the vessel at 500-µm intervals. Wall shear stresses of 1, 5, 10, and 15 dyn/cm2 were established by increasing perfusate flow using a syringe pump (Harvard Apparatus) and were calculated based on the average diameter of each vessel. Thus, in the presence of constant intraluminal pressure and constant diameter, a desired level of wall shear stress could be obtained solely by changing the flow rate.
Two hundred microliters of perfusate in the outflow tubing were collected at each level of shear stress in control and after administration of N-nitro-L-arginine methyl ester (L-NAME; 10–4 M), aminoguanidine (10–5 M), SOD (120 U/ml) plus catalase (80 U/ml), or 4,5-dihydroxy-1,3-benzenedisulfonic acid (tiron; 10–4 M). The chemicals were administered both intra- and extraluminally, and vessels were incubated for 30 min before reapplication of shear stress. In one set of experiments, perfusate was collected in control (shear stress: 15 dyn/cm2) and, after the vessel was incubated with SOD plus catalase, in the presence of shear stress (15 dyn/cm2) and simultaneous administration of ACh (10–5 M) to the chamber solution. Time control experiments showed no significant difference in perfusate nitrite within 3 h after repeated application of shear stress.
Nitrite (NO2–) formation in the perfusate was assessed by a fluorometric assay (21, 22) with a spectrofluorometer (SFM25, Kontron Instruments). Nitrate (NO3–) was converted to nitrite by the action of nitrate reductase (21, 22). Standard curves of nitrite (0–640 µM) were constructed using bicarbonate-5% CO2-buffered PSS as a vehicle. Inhibitors or O2–· scavengers did not interfere with the background reading. Changes in nitrite concentration in the chamber solution in response to the increases in shear stress or before and after administration of inhibitors or scavengers were insignificant. Because vessel size was different and because the aging process may have caused changes in vessel wall structure, the luminal surface area of vessels was calculated according to the length and average luminal diameter of each vessel and final nitrite production in response to shear stress was expressed as picomoles per millimeter squared per minute.
Chemiluminescent detection of O2–· production. O2–· production of isolated first-order mesenteric arteries was assayed by the lucigenin chemiluminescence method (23, 30). Vessels were equilibrated in PSS at 37°C for 30 min and then transferred into 5 µmol/l of lucigenin, and photon counts were recorded with a scintillation counter (LS 700, Beckman Instruments). Afterward, every vessel was completely digested with 50 µl of 1 N NaOH, and total protein was assayed. Final results are expressed as counts per minute per microgram of protein.
Protein expression with Western blotting.
After perfusion experiments, vessels were cut longitudinally to open the lumen and were snap frozen in liquid nitrogen. Samples (one vessel each) were solubilized in Laemmli buffer with 1% protease inhibitor cocktail (Sigma P-8340) and sonicated (2 x 60 s) before being boiled for 5 min. Proteins were separated on a SDS-PAGE gel (10% acrylamide), transferred to a polyvinylidene difluoride membrane, and probed with primary antibodies to phospho-eNOS (Ser1177, Cell Signaling), eNOS and mitochondrial SOD (Mn-SOD; BD Transduction Laboratories), intracellular SOD (Cu/Zn-SOD; Calbiochem), extracellular SOD (ECSOD) (Dr. Oury's laboratory), GAPDH (Chemicon International), and 
-actin (Novus Biologicala). Secondary antibodies were conjugated to horseradish peroxidase according to the Amersham ECL-Plus protocol.
In separate experiments, to analyze shear stress-induced phosphorylation of eNOS, a shear stress of 15 dyn/cm2 was applied to mesenteric arteries of 6- and 24-mo-old rats for a period of 20 min (according to our preliminary results, phosphorylation of eNOS reached its peak between 10 and 30 min in isolated, perfused rat mesenteric arteries). Vessels were then removed from the cannulae and snap frozen in liquid nitrogen for Western blotting analysis.
NOS activity. NOS activity of mesenteric arteries was assayed by measuring the rate of conversion of radiolabeled L-[3H]citrulline from L-[3H]arginine (Amersham) using an assay kit (Cat. No. 482700, Calbiochem). Two full-length mesenteric arteries were used in each sample. Vessels were cut longitudinally to expose the endothelial surface, and incubations were carried out at 37°C for 60 min. Final activity was normalized by the protein content of each sample.
SOD activity. SOD activity of mesenteric arteries was assessed by measuring the inhibition of pyrogallol autoxidation (20). First-order mesenteric arteries were isolated and pooled. Forty micrograms of protein from each rat were used, and the reaction was monitored spectrophotometrically at room temperature for 3 min. The activity was calculated against a standard curve of SOD (0–1.6 U/ml; S-2515, Sigma).
Statistical analysis. Data are expressed as means ± SE; n refers to the number of rats from which mesenteric arteries were isolated. Statistical analysis was performed using repeated-measures ANOVA followed by the Tukey-Kramer post hoc test and Student's t-test. Statistical significance was accepted at a level of P < 0.05.
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RESULTS |
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-actin. Protein expression of Cu/Zn-SOD and Mn-SOD was not different in arteries of young and aged rats. However, EC-SOD protein was decreased significantly (by 23%) in arteries of aged rats (Fig. 8B, 4 blots). The total activity of SOD in homogenates of pooled rat mesenteric arteries was also assessed. A significant reduction of SOD activity was found in arteries of aged rats compared with those of young rats (Fig. 8C), suggesting the presence of an attenuated antioxidant capacity in vessels of aged rats, which may lead to increases in O2–· production and a reduction in the bioavailability of NO.
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DISCUSSION |
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A few recent studies have demonstrated that aging impairs flow-induced dilation in isolated coronary (7) and skeletal muscle arterioles (25, 36). In the present study, we used isolated third-order mesenteric arterioles to investigate flow-induced dilation in 6- and 24-mo-old rats in response to an initial shear stress of 15 dyn/cm2 (Fig. 1). Although the size (basal or passive diameters) of vessels in the two groups of rats was significantly different, all vessels were subjected to an equal level of an initial shear stress. In this condition, vessels of aged rats exhibited a decreased ability to regulate wall shear stress compared with vessels of young rats. More importantly, the reduced inhibitory role of L-NAME in vessels of aged rats and the similar dilation to SNP in vessels of young and aged rats demonstrate that the impairment in flow-induced dilation in vessels of aged rats is mainly due to a decreased endothelium-derived NO-induced dilation. Similar to third-order arterioles, in first-order arteries, shear stress-induced release of NO was also reduced in aged rats compared with young rats. To investigate the direct relationship between levels of shear stress and endothelium-derived NO release and the possible mechanisms of the impairment in the function of aged vessels, we used isolated mesenteric arteries in the rest of the experiments.
In agreement with evidence obtained previously by us (7) and others (13, 33), the present results indicate an increased formation of O2–· in nonstimulated and stimulated conditions in mesenteric arteries of aged rats. The possible sources of the increased formation of O2–· in aged vessels was not investigated in the present study. Previous studies, however, demonstrated that O2–· derived from NAD(P)H oxidase (30), xanthine oxidase (18), eNOS uncoupling (16), and other causes (3) all impaired endothelial dilator functions. Among these, NAD(P)H oxidase seems to be the major source of the excessive O2–· in vascular aging (7, 13). We (7) demonstrated previously that there is a severalfold increase in the basal formation of O2–· in coronary arteries of aged rats, which was inhibited by diphenyleneiodonium, an inhibitor of NAD(P)H oxidase. It is not clear, however, whether the increased NAD(P)H oxidase-derived O2–· measured in basal conditions accounts for the diminished vasodilatation after stimulation by increased intraluminal flow (7). In the present study, basal production of O2–· in noncannulated and nonstimulated arteries was 40% greater in vessels of aged rats compared with young rats (Fig. 5B); moreover, in aged vessels, shear stress-induced perfusate nitrate, derived from the reaction of NO and O2–· forming peroxynitrite in oxygenated PSS (2), was 300% greater than in those of young animals (Fig. 5A). Also, scavenging O2–· with tiron or SOD nearly doubled shear stress-induced perfusate nitrite in aged vessels, mostly at high shear stress levels (Fig. 4). Thus these data imply that besides the basal release of O2–·, shear stress elicits an additional increase in O2–· formation, a phenomenon that only occurs in aged vessels. It has been shown previously that hemodynamic forces affect O2–· formation in certain conditions. In our previous study (15), we demonstrated that an acute high intra-arteriolar pressure increased O2–· formation and consequently reduced NO-mediated shear stress-induced dilation. Others showed that exposure of cultured endothelial cells to shear stress increased the production of O2–· (8, 14) and that the increased O2–· was due to enhanced NADH oxidase activity (8). A recent study (28) using a real-time recording technique further demonstrated a concomitant endothelial generation of O2–· and NO by shear stress (28). A shear stress-induced increase in O2–· formation in the aged vasculature may have particular clinical importance because it impairs flow-induced dilation resulting in further increases in shear stress and O2–· formation.
Similar to our previous findings, in which tiron and exogenous SOD did not fully restore flow-induced dilation in aged coronary vessels (7), in the present study, we found that tiron and SOD plus catalase failed to completely normalize shear stress-induced NO release in aged vessels (Fig. 4). Additionally, tiron and SOD had no influence on perfusate nitrite in vessels from either group of rats in response to stimulation by low shear stress, when there was significant difference in nitrite production between young and aged rats (Figs. 2 and 4). Furthermore, total perfusate nitrite (NO2– + NO3–), which represents NO and O2–·-inactivated NO, in response to 15 dyn/cm2 of shear stress was significantly less in arteries of aged rats than in those of young rats (Fig. 5A). These data suggest that the synthesis of NO in response to stimulation by shear stress is decreased in the endothelium of aged vessels. Thus both decreased activation of eNOS by shear stress and increased scavenging of NO by O2–· contribute to the reduced shear stress-induced release of NO in mesenteric arteries of aged rats.
Although several previous studies reported that eNOS mRNA (6) and eNOS protein expression (7, 35) were reduced in the aging coronary and skeletal muscle vasculatures, in the present study eNOS protein expression was not significantly different in mesenteric arteries of young and aged rats (Fig. 6, A and B). Furthermore, basal eNOS activity, measured by the conversion of L-[3H]arginine to L-[3H]citrulline in noncannulated and nonstimulated vessels, was comparable between vessels of the two age groups (Fig. 6C). More importantly, the administration of ACh (10–5 M) via a receptor-mediated, calcium-dependent enhancement of NO synthesis in the presence of 15 dyn/cm2 of shear stress increased perfusate nitrite significantly in arteries of the aged rats, leading to a nitrite level that was comparable to that released by vessels of young rats. Therefore, in mesenteric arteries of aged rats, shear stress-induced synthesis of NO is reduced, but the capacity of eNOS to synthesize NO is preserved. We interpret these paradoxical results to mean that it is the signaling cascade eventuating in the phosphorylation of eNOS that specifically mediates the response to shear stress in the endothelium of aged arteries that is likely to be impaired. This interpretation is supported by the results shown in Fig. 7 demonstrating that the level of phosphorylation of eNOS in response to a shear stress of 15 dyn/cm2 was decreased in vessels of aged rats. It is known that aging is associated with structural changes of the vascular wall, resulting in arterial stiffness (12, 24). A recent study (27) indicates that wall stiffness suppresses shear-induced phosphorylation of Akt and consequently eNOS. In this context, endothelial function and mechanosignaling of shear stress may well be altered by changes in the compliance of vascular wall during the process of aging. Some recent studies suggested that an increased nitration of proteins by peroxynitrite within the aged vascular wall (7, 34) could alter protein structure and function, including uncoupling of eNOS (16, 37), but whether this alteration plays a role in the impaired shear stress-stimulated NO release observed in the present study is not known. On the other hand, a decreased serum L-arginine has been reported to have a role in age-related NO deficiency (29), which, however, could be excluded in the present study on the basis of the maintained basal and ACh-induced increase in perfusate nitrite in aged vessels (Fig. 8D). A possible increased expression of iNOS (5, 7) is also unlikely to play a role because inhibition of iNOS had virtually no effect on perfusate nitrite in vessels of the two groups of rats.
Effects of aging on SOD expression and activity in the vascular wall are not well known, albeit a specific contribution of an attenuated activity of SOD to the impairment of endothelial function in certain pathological conditions, such as coronary artery disease (17) and heart failure (18), has been reported. In the present study, we found that expression of Cu/Zn-SOD and Mn-SOD was not reduced, but that of ECSOD was significantly reduced, paralleled by a reduced total SOD activity in vessels of aged rats (Fig. 8). These results provide evidence to support our conclusion that age-related downregulation of ECSOD contributes to the reduced NO bioavailability in response to shear stress. This is supported by the finding that ECSOD is the predominant isozyme of SOD in arteries (11, 26) and has recently been shown to be a major regulator of NO activity in arteries (9). Moreover, reduced activity of the other two isoforms of SOD, although their expression remains normal, may also play a role. Indeed, some studies demonstrated a significantly enhanced tyrosine-nitrated Mn-SOD level in aging (34) that leads to a decreased Mn-SOD activity (19), followed by impaired NO bioavailability.
In summary, downregulation of ECSOD expression and SOD activity, enhanced production of superoxide, and an impaired shear stress-dependent signaling pathway are likely to be responsible for the age-related reduction in NO release in response to shear stress in isolated mesenteric arteries. Thus a loss of a balance between oxidant and antioxidant effects, which may interfere with the function of signaling proteins or coupling of the eNOS reaction, seems to be the mechanism that underlies endothelial dysfunction characteristic of vascular senescence.
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FOOTNOTES |
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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.
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P < 0.05 compared with corresponding data obtained from vessels of 6-mo-old rats. B: basal level of superoxide formation as determined by lucigenin chemiluminescence (5 µM) in mesenteric arteries of 6- and 24-mo-old rats. CPM, counts per minute. *P < 0.05.
