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Am J Physiol Heart Circ Physiol 290: H1259-H1263, 2006. First published November 11, 2005; doi:10.1152/ajpheart.00990.2005
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Age-associated impairment in vasorelaxation to fluid shear stress in the female vasculature is improved by TNF-{alpha} antagonism

Ivan A. Arenas, Yi Xu, and Sandra T. Davidge

Perinatal Research Centre, Departments of Obstetrics and Gynecology and of Physiology, University of Alberta, Edmonton, Alberta, Canada

Submitted 16 September 2005 ; accepted in final form 1 November 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Aging is associated with alterations in vascular homeostasis, including a reduction in flow-mediated vasodilation, which in women is related to the onset of menopause. We previously found that in female animals, aging is associated with an increase in TNF-{alpha}. Thus we investigated the role of in vivo TNF-{alpha} inhibition on vascular responses to shear stress in aging female rats. Mesenteric arteries (~150 µm) were isolated from young (3 mo) and ovariectomized Sprague-Dawley female rats approaching reproductive senescence (12 mo) treated with either placebo or a TNF-{alpha} inhibitor (etanercept; 0.3 mg/kg) and were mounted on a pressure myograph system. Vessels were equilibrated at an intraluminal pressure of 60 mmHg and then preconstricted with phenylephrine at ~70% of their initial diameter. Perfusate flow was increased in steps from 0 to 150 µl/min. Compared with young vessels, aged vessels have a decrease in flow-mediated dilation [maximal dilation (means ± SE): 52 ± 4 vs. 24 ± 15%; P < 0.05], which was improved by TNF-{alpha} inhibition. Moreover, in aged vessels maximal dilation to flow was achieved at higher levels of shear stress compared with young vessels. In all groups, flow-mediated dilation was abolished by either endothelial removal or nitric oxide synthase inhibition with NG-nitro-L-arginine methyl ester. However, the modulation by NG-nitro-L-arginine methyl ester was reduced in vessels from aged animals compared with young animals but was improved in the etanercept-treated aged animals. In vivo chronic TNF-{alpha} inhibition improves flow-mediated arterial dilation in resistance arteries of aged female animals.

tumor necrosis factor-{alpha}; estrogen deficiency; flow dilation; nitric oxide; endothelium

AGING IS ASSOCIATED with alterations in vascular function and higher risk of cardiovascular disease. In women, age-associated alterations in vascular function are related to the onset of menopause (10, 36). Inflammatory factors are involved in the pathogenesis of vascular disorders, and some evidence suggests that cytokines may mediate some of the vascular changes associated with aging. Indeed, we recently reported that in female rats, aging is associated with an increase in the levels of TNF-{alpha}, a proinflammatory cytokine, which results in alterations of vascular function (1).

Shear stress on the vascular wall is an important mechanism that regulates vascular homeostasis, including vascular tone (29). For instance, in isolated resistance arteries, wall shear stress elicited by intraluminal flow can induce vasodilation of constricted arteries (6). Flow-dependent vasodilation is mediated by endothelium-derived factors such as nitric oxide (NO) (5). In fact, the primary physiological stimulus for the production of NO production by the endothelial NO synthase (eNOS) is fluid shear stress (8, 27).

Aging has been associated with alterations in responses to shear stress. Although the mechanisms remain unclear, it has been hypothesized that a reduction in NO availability may mediate these alterations. NO modulates vascular levels of shear stress by inducing arterial dilation (29). Thus reduction in NO availability is associated with either a decrease in vasodilation to flow or constriction (35). This could lead to an increase in the levels of shear stress that may cause endothelial damage and increase peripheral resistance. Accordingly, flow-induced vasorelaxation is decreased in hypertensive disorders (11, 23). Moreover, a decrease in flow-dependent relaxation is an independent predictor of future cardiovascular events (34).

Inflammatory factors such as TNF-{alpha} play an important role in the pathogenesis of vascular disease (7). In women, aging is associated with an increase in TNF-{alpha} levels (25), which may reduce NO availability (1). Thus we investigated the effect of aging on vascular responses to shear stress and evaluated the role of selective TNF-{alpha} inhibition on flow vasodilation in aged female animals. We hypothesized that aged vessels are less sensitive to the vasodilator effects of shear stress caused by a decrease in NO availability and that these alterations could be improved by TNF-{alpha} inhibition.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animal model. This study was approved by the University of Alberta Health Sciences Animal Policy and Welfare Committee and was in accordance with the Canadian Council on Animal Care. Female Sprague-Dawley rats were obtained from Charles River (Montreal, Quebec, Canada) and were housed in the facilities of the University of Alberta until experimentation at 12–15 mo of age. Briefly, this age was chosen because the animals have attained their state of reproductive senescence (i.e., similar to the postmenopausal state of women). Moreover, to decrease the confounding effect of variable estrogen levels characteristic in these aged animals, we removed the ovaries and randomly assigned the aged animals to different treatments for 4 wk. We have previously described this model (1–3, 14, 32, 37, 38, 40).

Experimental design. To investigate the effects of aging on vascular function and TNF-{alpha} levels, intact cycling animals (4 mo old; proestrus) were used as a control (young; n = 6). Moreover, to evaluate whether the age-associated increase in TNF-{alpha} levels in female rats results in changes of vascular function, aged rats were treated with either etanercept (a TNF-{alpha} inhibitor, Immunex, Thousand Oaks, CA), subcutaneously administered at 0.3 mg/kg, three times a week (n = 9), or placebo (subcutaneous injection of double-distilled H2O, n = 9) for 4 wk before the experimentation. Etanercept is composed of the extracellular ligand-binding portion of the human 75-kDa (p75) TNF-{alpha} receptor 2. Thus etanercept binds and inactivates circulating TNF-{alpha}. The etanercept dose was calculated based on effective TNF-{alpha} inhibition from previous studies in humans and rats (15, 16), including our own studies in this model (1, 4). Rats were euthanized by exsanguination while under anesthesia (pentobarbital sodium, ~60 mg/kg body wt). A blood sample was taken and serum was obtained by centrifugation. Samples were snap-frozen (–80°C) for subsequent measurement of TNF-{alpha} levels. Serum bioactive TNF-{alpha} was measured using the L929-8 bioassay as previously described (1).

Vessel preparation. A portion of the mesentery was excised and immersed in ice-cold HEPES-buffered physiological saline solution (HEPES-PSS), which contained the following (in mmol/l): 142 NaCl, 4.7 KCl, 1.17 MgSO4, 1.56 Ca2Cl, 1.18 KH2PO4, 10 HEPES, and 5.5 glucose. Small (~150 µm) mesenteric arteries were dissected free from surrounding fat and connective tissue and transferred to a dual-chamber pressure myograph (Living Systems Instrumentation, Burlington, VT). The chamber contains a pair of glass micropipettes filled with HEPES-PSS at room temperature. After the vessel was mounted on the proximal pipette and secure with sutures, it was gently flushed with physiological buffer (10 µl/min) to clear blood from the lumen. The other end of the vessel was then mounted in the distal pipette. After mounting was completed, all arteries were examined for ability to maintain pressure. Any decrease in pressure indicated a leak and a new artery was dissected. The second-order mesenteric arteries were equilibrated in warm HEPES-PSS (which was added to the baths of the system at 10-min intervals) for 30 min at an intraluminal pressure of 60 mmHg at zero flow.

Vascular function studies. Vessel integrity was evaluated by constriction to a single bolus of phenylephrine (0.1 µmol/l) and relaxation to methacholine (1 µmol/l) to test endothelium-dependent relaxation. After the equilibration period, vessels were preconstricted with phenylephrine to ~70% of their initial internal diameter. Flow-diameter relationship was then established by step increases in flow from 0 to 150 µl/min. Flow was established at a constant intravascular pressure (60 mmHg) by controlling proximal and distal pressures to keep midpoint luminal pressure constant. Intraluminal pressures were controlled in a two-chamber arteriograph (Living Systems Instrumentation) through two servo-controlled peristaltic pumps connected to the cannula via a pressure transducer. A digital filar eyepiece (Lasico, Los Angeles, CA) mounted on a compound microscope was used to measure arterial lumen diameters as previously described (13).

Flow rate was calibrated with a Harvard perfusion pump in the range of 0–200 µl/min. Each flow step was maintained for ~120 s before the diameter of the arterioles was measured. After control flow-diameter curves were obtained, vessels were preincubated with the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 100 µmol/l; Calbiochem) (28). Then, after 30 min of incubation, changes in diameter in response to step increases in flow were reassessed. At the end of each experiment, diameter measurements were conducted in the absence of extracellular calcium to determine artery passive diameter.

The role of endothelium on flow responses was evaluated by mechanical removal of the endothelium by bubbling air through the vessels for 10 min. Confirmation of complete endothelium removal was assessed pharmacologically with a bolus dose of 1 µmol/l methacholine. Sodium nitroprusside (1 µmol/l) was used to evaluate viability in vessels that did not respond to methacholine. Percentage of relaxation was calculated after any flow step by using the following formula: %relaxation = 100 x (D1 – D2)/(D3 – D2), where D1 is the internal diameter in Ca2+-free medium, D2 is the internal diameter after preconstriction with phenylephrine, and D3 is the internal diameter at any flow step. Shear stress was calculated according to the following equation: shear stress (dyn/cm2) = 4{eta}Q/{pi}r3, where {eta} is viscosity of the perfusate (PSS = ~0.007 poise at 37°C), Q is flow (µl/min), and r is radius (cm) (17).

Data analysis. Data are presented as means ± SE. Two-way repeated-measures ANOVA was used to assess differences in vasodilator responses to flow steps between groups and to test the effect of L-NAME. Student's t-test was used to test differences in maximal dilation between two groups. Tests were considered significant at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Aged female rats had higher serum levels of TNF-{alpha} compared with young rats (28 ± 6 and 7 ± 3 pg/ml, respectively; P < 0.05). However, treatment with etanercept reduced TNF-{alpha} levels similar to that of young rats (10 ± 4 pg/ml).

Effects of aging and TNF-{alpha} inhibition on vascular responses to shear stress. Passive arterial diameters (in µm) at 60 mmHg were 288 ± 21 in young animals and 301 ± 18 in aged animals. Compared with young animals, aged animals had a blunted vasodilator response to flow (Fig. 1A; P = 0.03). Percentage of maximal dilation was 24 ± 15% and 52 ± 4% in aged and young vessels, respectively (Fig. 1B; P = 0.04). Flow rates (0 to 150 µl/min) resulted in levels of shear stress ranging from 0 to 45.6 ± 13.2 dyn/cm2 in young animals and from 0 to 265 ± 81 dyn/cm2 in aged animals (Fig. 2; P = 0.04). Maximal relaxation was achieved at higher levels of shear stress in aged animals compared with young (70 ± 31 and 19 ± 6 dyn/cm2 respectively; Fig. 2; P < 0.05).


Figure 1
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  		Fig. 1. Effects of aging in female rats on flow-mediated vasodilation of mesenteric arteries. A: flow-mediated vasodilation; n = 6 for young animals, and n = 9 for aged animals. B: percentage of maximal vasodilation. Bars represent means ± SE. *P < 0.05 vs. young.

 

Figure 2
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  		Fig. 2. Shear stress levels and vasodilation to flow of mesenteric arteries from young (n = 9) or aged animals (n = 9). Symbols represent means; horizontal bars represent SE of shear stress and vertical bars represent SE of % of flow dilation.

 
TNF-{alpha} inhibition with etanercept improved flow vasodilation in aged animals (Fig. 3A). Maximal dilation was greater in etanercept-treated animals compared with aged animals treated with placebo (65 ± 15% and 22 ± 13%, respectively; Fig. 3B; P < 0.05). Levels of shear stress in vessels from etanercept-treated animals were reduced compared with aged animals treated with placebo (Fig. 4; P < 0.05). Passive arterial diameter did not differ between aged groups (placebo and etanercept: 288 ± 14 and 314 ± 20 µm, respectively).


Figure 3
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  		Fig. 3. Effect of in vivo TNF-{alpha} inhibition with etanercept (Etan) on flow-mediated vasodilation in aged rats. A: flow responses of mesenteric arteries. B: percentage of maximal vasodilation. Circles represent vessels from placebo-treated animals (n = 9). Triangles represent vessels from animals treated with Etan (n = 9). Bars represent means ± SE. *P < 0.05.

 

Figure 4
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  		Fig. 4. Shear stress levels and vasodilation to flow of mesenteric arteries from aged rats treated either with placebo (circles; n = 9) or Etan (triangles; n = 9). Symbols represent means; horizontal bars represent SE of shear stress and vertical bars represent SE of % of flow dilation.

 
Effects of endothelial removal and NOS inhibition. Endothelium-denuded vessels did not dilate to flow and showed vasoconstriction (data not shown). NOS inhibition with L-NAME abolished the vasodilation of vessels from young (Fig. 5A) and aged animals (Fig. 5, B and C). Indeed, differences in vasodilation to flow among groups were not longer significant after L-NAME pretreatment (P = 0.3). However, the net effect of L-NAME on maximal vasodilation was greater in young animals and aged animals treated with etanercept compared with aged-placebo animals (Fig. 5).


Figure 5
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  		Fig. 5. Effects of nitric oxide synthase (NOS) inhibition on flow-mediated vasodilation. Flow responses of mesenteric arteries from young animals (A; n = 6) or aged rats treated either with placebo (B; n = 9) or Etan (C; n = 9) in the absence (solid symbols) or in the presence (open symbols) of in vitro NG-nitro-L-arginine methyl ester (L-NAME, 100 µmol/l; n = 3). *P < 0.05.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The primary finding of this work is that TNF-{alpha} inhibition improves flow-mediated vasodilation in isolated resistance arteries of aged female rats by increasing NO availability. Vasodilation to flow in young and aged animals was abolished by either NOS inhibition with L-NAME or endothelial removal. This indicates that endothelial NO is a primary mediator of flow-mediated vasodilation in both young and aged animals. However, NOS inhibition resulted in a decrease in vasodilation, which was significantly larger in young rats compared with aged-placebo animals. Furthermore, the improvement in vascular relaxation achieved in aged animals with TNF-{alpha} inhibition was also accompanied by an increase in NO-mediated relaxation, as shown by an increase in the delta change of relaxation before and after L-NAME in etanercept-treated animals compared with placebo animals. This may suggest that the greater flow/shear stress-induced dilation of vessels of young and etanercept-treated animals is likely to be due to a greater release of NO.

These results agree with previous findings suggesting that endothelial NO is a primary mediator of flow-dependent relaxation in mesenteric arteries (18, 26) and that vasodilation to agonistic stimulus is reduced with aging (19, 30, 33). However, most of these studies have been conducted in male animals, and only few have demonstrated these alterations in aged female animals (33).

Shear stress regulates the expression of eNOS (21), and during physiological conditions, it stimulates the basal release of endothelial NO (22, 23), which opposes several vasoconstrictor stimuli including neurohormonal stimulation. Shear stress-induced NO release is mediated by acute phosphorylation of eNOS by protein kinases (8, 9). However, in pathological conditions a decrease in NO availability results in chronic vasoconstriction and higher levels of shear stress (23). Although the decrease in vasorelaxation with aging has been attributed to higher levels of oxidative stress, which in turn lead to a decrease in NO availability, the mechanisms that trigger these alterations remain unclear.

TNF-{alpha} is a proinflammatory cytokine involved in the pathogenesis of vascular disorders. TNF-{alpha} reduces NO availability by decreasing eNOS expression (39) or by increasing NO inactivation by superoxide anion through stimulation of NAD(P)H oxidase (20). TNF-{alpha} formation is regulated by estrogen (31), and the decline of the ovarian function with menopause is associated with spontaneous increases in TNF-{alpha} levels. In previous studies we have found that TNF-{alpha} inhibition with etanercept improved agonist-mediated vasorelaxation and increased eNOS expression in aged female animals (1). In this study, TNF-{alpha} inhibition was associated with an increase in the vasodilator responses to shear stress in aged animals. Thus taken together these observations suggest that interactions between TNF-{alpha} and NO during aging may lead to a decrease in the vasodilator capacity of resistance arteries.

Regulation of wall shear stress contributes to vascular resistance. Although moderate levels of shear stress are vasculoprotective, higher levels of shear stress may cause endothelial damage and increase peripheral resistance, which are features of hypertensive disorders. In this study, maximal relaxation in young vessels occurred at lower levels of shear stress compared with aged animals. Moreover, vessels from aged animals have an increase in wall shear stress when compared with young animals subjected to similar flow rates. These observations may suggest that aged vessels are less sensitive to shear stress-induced vasodilation. Interestingly, improvement in NO modulation in aged vessels with etanercept resulted in a reduction of shear stress levels. However, the levels of shear stress at which maximal dilation occurred did not differ between aged groups, suggesting that there could be alterations in the signaling pathway for NO release in aged animals.

The mechanisms by which flow is translated into cellular signaling are still unclear. It has been postulated that a mechanotransducer within the cell membrane would trigger an enzymatic cascade (24). Moreover, it has also been proposed that shear stress signaling is mediated by components of the cytoskeleton such as the integrins (12). Therefore, alterations in signaling mechanisms or structural changes in aged vessels could be involved on determining the point of stress needed for maximal relaxation. This study provides the foundation for future studies to address the specific mechanisms.

In summary, we have shown that in female rats, NO is the primary mediator of flow-dependent relaxation in isolated mesenteric arteries. Moreover, aging is associated with a reduction in shear stress-induced vasodilation, which was improved by TNF-{alpha} inhibition, this effect being related to an increase in NO modulation of vasorelaxation. Taken together, these findings suggest that upregulation of TNF-{alpha} levels with aging is associated with a decrease in flow-mediated vasodilation leading to higher levels of shear stress that may result in vascular disease.


   ACKNOWLEDGMENTS
 
The Canadian Institute for Health Research supported this study. S. T. Davidge is a Canada Research Chair in Women's Cardiovascular Health and an Alberta Heritage Foundation for Medical Research (AHFMR) Senior Scholar. I. A. Arenas is a AHFMR scholarship recipient and a Fellow in Tomorrow's Research Cardiovascular Health Professionals.


   FOOTNOTES
 

Address for reprint requests and other correspondence: S. T. Davidge, Perinatal Research Centre, 220 HMRC, Univ. of Alberta, Edmonton, Alberta, Canada T6G 2S2 (e-mail: sandra.davidge{at}ualberta.ca)

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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J. Physiol., September 15, 2006; 575(3): 821 - 832.
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