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-estradiol in hypercholesterolemic rabbits with
severe endothelial dysfunction
1 University of Sao Paulo, Sao Paulo, Brazil 01246-903; and 2 Berlex Biosciences, Cardiovascular Department, Richmond, California 94804
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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17
-Estradiol prevents early vascular lesion
development and may also affect advanced atherosclerosis. To test the
antiatherosclerotic effect of estrogen under conditions that resemble
more advanced human atherosclerosis with severe endothelial
dysfunction, we have investigated the effect of 17-estradiol in
hypercholesterolemic rabbits treated with the nitric oxide synthase
inhibitor
N
-nitro-L-arginine
methyl ester (L-NAME). Chronic
L-NAME administration attenuated
endothelial nitric oxide (EDNO)-mediated vascular responses leading to
significantly accelerated atherosclerotic plaque development. 17-Estradiol treatment alone inhibited aortic lesion formation with
concurrent increase in EDNO-mediated responses. The beneficial effect
of estrogen persisted in the
L-NAME-treated rabbits,
suggesting that the antiatherogenic action of 17-estradiol involves
NO-independent mechanisms as well. Serum cholesterol levels were not
altered by any of the treatments. 17-Estradiol treatment
significantly increased EDNO production under these conditions as well.
The reduction in plaque size by 17-estradiol was always accompanied by increased EDNO production, suggesting a strong association between
these two events. The results demonstrate that estrogen treatment may
exert protection against atherosclerosis even in patients with severe
endothelial dysfunction.
nitric oxide; atherosclerosis; N-nitro-L-arginine
methyl ester
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ENDOTHELIAL DYSFUNCTION, impaired endothelial nitric
oxide (EDNO)-mediated vasorelaxation, is an early functional sign of clinical atherosclerosis, indicating the loss of vascular wall integrity (29). Endothelial cell activation or diminished EDNO formation in regions of atherosclerotic lesions of the vascular wall is
considered to play a major role in the progression of atherosclerotic
plaques (4). Chronic inhibition of nitric oxide (NO) formation by
N-nitro-L-arginine
methyl ester (L-NAME)
accelerated atherosclerotic plaque formation in hypercholesterolemic
rabbits (3, 22), demonstrating that the lack of EDNO is a key
progression factor in the development of atherosclerosis in this
species. Studies have also demonstrated that administration of
exogenous L-arginine, the
physiological precursor of NO, restored endothelium-dependent relaxation in hypercholesterolemic humans (6) and decreased aortic
lesion formation in cholesterol-fed rabbits (2, 5, 17, 27).
The antiatherogenic properties of 17-estradiol have been well
documented in epidemiological and clinical investigations as well as in
animal studies, including the hyperlipidemic rabbit (19, 23). These
studies suggest that beyond its lipid-lowering effect, 17-estradiol
has direct vascular effects, and the vascular endothelium may be a
target of its action leading to cardiovascular protection. Because of
its beneficial cardiovascular actions, EDNO seems to be an ideal
mediator of the antiatherosclerotic effect of 17-estradiol. Indeed,
upregulation of NO synthase (NOS) III in response to estrogen treatment
has been reported both in vitro (13, 14, 20) and in vivo (9, 28).
Therefore, it is conceivable that 17-estradiol treatment can exert
cardiovascular protection even in stages of atherosclerosis with severe
endothelial dysfunction.
To test this hypothesis, the present study was designed to investigate
the effect of 17-estradiol in ovariectomized, hypercholesterolemic rabbits in which severe endothelial dysfunction, diminished
EDNO-mediated vasorelaxation, was induced by chronic inhibition of NOS.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
Thirty-two female New Zealand White rabbits, weighing 3-3.5 kg, were ovariectomized under ketamine anesthesia. After a 1-wk recovery period following surgery, animals were fed by 1% cholesterol-containing rabbit food. One week after the start of high-cholesterol feeding, rabbits were randomly selected into four treatment groups (each consisting of 8 animals): 1) vehicle control group (VC), receiving daily subcutaneous injections of 0.2 ml of benzyl benzoate-castor oil (1:9 mixture); 2) L-NAME group, provided with 100 µg/ml L-NAME in the drinking water; 3) 17-estradiol
group (E2), injected with daily
30 µg of 17-estradiol dissolved in vehicle (0.2 ml); and 4)
L-NAME + E2 group, supplied with 100 µg/ml L-NAME in drinking water
and injected with daily 30 µg of 17-estradiol. The animals were
housed individually and provided daily with fresh drinking water,
either with or without L-NAME,
ad libitum. The dose of L-NAME
was selected based on earlier reports (3, 22) and pilot studies using
50, 100, and 150 µg/ml L-NAME
via subcutaneous administration to ovariectomized rabbits on normal
food. Three rabbits were tested for each concentration. Inhibition of
EDNO-mediated responses was not different between the 100 and 150 µg/ml L-NAME-treated group,
and after 1-wk administration of the NOS inhibitor, no significant
differences could be measured in mean arterial blood pressure of
ketamine-anesthetized rabbits (data not shown). Water intake was monitored daily and weight gain was monitored weekly. Food
intake of the animals was limited to daily 150 g of
cholesterol-containing rabbit food. Under these controlled
circumstances, there was no significant difference in weight gain,
water intake, and total serum cholesterol level of the animals from the
different treatment groups (Table 1). The
study was conducted according to protocols approved by the Animal Care
Committee at Berlex Biosciences, in agreement with the recommendation
of the American Association for the Accreditation of Laboratory Animal
Care.
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Determination of Atherosclerotic Vascular Lesions
Animals were killed after 7 wk of treatment (8 wk on 1% cholesterol diet). At death, blood was collected to measure serum cholesterol and estrogen levels, and the thoracic aorta was dissected. The proximal part of the aorta, including the aortic arch, was fixed in 10% Formalin. After being cleaned from the adherent connective tissues, the aortas were cut open longitudinally and pinned down individually on silicon-coated petri dishes, intimal surface up. Atherosclerotic plaque areas (fatty lesions) were visualized by staining the aortas with oil-red O. Total and plaque-covered areas were quantified by image analysis of the scanned photographic pictures.Endothelium-Dependent Vascular Responses
Four rings of the distal end of each thoracic aorta, from the same animals in which the plaque areas were determined, were immediately placed in cold physiological saline solution of the following composition (in mM): 141 Na+, 125 Cl
, 2.5 Ca2+, 4.7 K+, 0.76 Mg2+, 1.7 H2PO4,
25 HCO3, 0.026 EDTA, 11 glucose, and 5 HEPES. After the adherent connective tissues were cleaned off, the
endothelium was removed in two of the four rings by rubbing the intimal
surface with a cotton swab. The rings were then mounted in organ
chambers (Schuler, Hugo Sachs Elektronic, March-Hugstetten, Germany),
and changes of isometric tension in response to drug treatment were
measured with force transducers (Grass FT03, Hugo Sachs) and recorded
by a four-channel recorder (Graphtec Linearcorder WR 3310, Hugo Sachs).
Successful removal of the endothelium was confirmed by the absence of
relaxation in response to ACh (1 µM) in phenylephrine (PE; 1 µM)-contracted rings. Rings with and without endothelium were studied
in parallel. Basal EDNO production was estimated by measuring
N-nitro-L-arginine
(L-NNA; 100 µM)-induced,
endothelium-dependent tension development in PE-contracted
(EC50 = 3 µM) aortic rings (25).
Stimulated EDNO release was estimated by dose-dependent endothelium-mediated relaxation evoked by ACh (10 nM-10 µM) in rings
contracted with 3 µM PE. These studies were performed in the presence
of 10 µM indomethacin to block the production of vasoactive
prostanoids. Relaxation to nitroglycerin (NG; 1 nM-1 µM)
was also investigated in rings without endothelium to test the effect
of treatments on the sensitivity of the vascular smooth muscle to NO.
Plasma Cholesterol and 17-Estradiol
Determination
Materials
ACh chloride, NG, PE, L-NAME, and L-NNA were obtained from Sigma Chemical (St. Louis, MO). Fresh stock solutions, used for the contractility studies, were prepared freshly before each experiment. All stock solutions were made in distilled water, and further dilutions were made in physiological salt solution, except indomethacin, which was dissolved in Na2CO3 (0.2 M) and distilled water (1:9). 17-Estradiol was provided by
Schering (Berlin, Germany). 17-Estradiol was dissolved in benzyl
benzoate and castor oil as a 1:9 mixture. This solution was prepared
fresh every 2 wk during the study. Benzyl benzoate and castor oil were
obtained from Sigma Chemical. 17-Estradiol and its vehicle were
administered as a subcutaneous injection in a 0.2-ml volume daily for 7 wk.
Calculations and Statistical Analysis
The concentration of PE causing half-maximal contraction (EC50) was calculated from full dose-response curves. Relaxation evoked by ACh and NG is expressed as percent inhibition of the contraction by PE. Lesion area is expressed as a percentage of the total luminal surface of the thoracic aorta. Results are presented as means ± SE for the number of experiments on different animals (n) indicated. Statistical analyses of the data were performed by ANOVA or Student's t-tests for unpaired observations. Data were considered to be significantly different at a value of P < 0.05.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Atherosclerotic Vascular Lesions
Cholesterol feeding for 8 wk resulted in significant fatty streak formation in the thoracic aortas of all rabbits. In the VC group (n = 8), 76 ± 8% of the aortic arch (Fig. 1A) and 30.2 ± 4% of the luminal surface of the thoracic aorta (Fig. 1B) were covered with atheromatous plaques as determined by image analysis of the scanned photograph of the oil-red O-stained segments. Chronic L-NAME treatment (n = 8) significantly (P < 0.05) increased the lesion-covered areas to 95.2 ± 3% in the aortic arch and to 47.3 ± 8% in the thoracic aorta compared with controls (Fig. 1). 17-Estradiol treatment (n = 8)
significantly (P < 0.0001) inhibited
the development of aortic lesions compared with both the VC and
L-NAME groups. The calculated
plaque-to-surface area ratio was 47.1 ± 8% in the aortic arch and
4.1 ± 1% in the thoracic aorta, respectively (Fig. 1).
17-Estradiol administration to the
L-NAME-treated rabbits (n = 8) resulted in significant
decrease of the plaque-covered areas in both the aortic arch (57.1 ± 8%) and the thoracic aorta (10 ± 2%) compared with vessels
isolated from the L-NAME-treated animals (Fig. 1). The plaque-to-surface area ratio was not
statistically different from the
E2 group.
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The percent reduction in plaque size by 17-estradiol treatment was
not significantly different in the absence (aortic arch, 20.5 ± 10%; thoracic aorta, 74 ± 26%) and presence of
L-NAME treatment (aortic arch,
27.1 ± 7%; thoracic aorta, 60.1 ± 12%), respectively. Figure
2 shows photographs of aortas isolated from
representative animals of each of the four treatment groups.
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Endothelium-Dependent Vascular Responses
Basal EDNO release.
Endothelium-dependent increase in isometric tension in response to 100 µM L-NNA (basal EDNO
production) of aortic rings contracted with 3 µM PE is shown in Fig.
3. The mean ± SE contractions of the
vessels in response to 3 µM PE in the four treatment groups were as
follows: VC, 2.95 ± 0.07 g;
L-NAME, 3.03 ± 0.08 g;
E2, 3.18 ± 0.04 g;
L-NAME + E2, 2.96 ± 0.07 g
(n = 8 in each group). These values
were not statistically different. Basal EDNO-mediated responses were
significantly (P < 0.05) diminished
in rings isolated from the
L-NAME-treated rabbits compared
with controls. The responses in the
L-NAME-treated group were not
statistically different from those obtained in endothelium-denuded
segments (data not shown), indicating complete inhibition of basal EDNO
production. This observation demonstrates that chronic treatment with
L-NAME results in severe
inhibition of unstimulated NOS III activity in rabbit thoracic aortas.
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-Estradiol administration to the
L-NAME-treated rabbits resulted
in significant increase in basal EDNO release even in the presence of
the NOS inhibitor compared with the
L-NAME-treated group, although
EDNO-mediated responses became significantly
(P < 0.05) suppressed compared with
the E2 group.
The percent increase in basal EDNO release in response to chronic
17-estradiol treatment was not statistically different in the
absence (85.7 ± 9%) and presence of
L-NAME treatment (115 ± 34%).
Stimulated EDNO release.
Endothelium-dependent relaxation of thoracic aortic rings to ACh is
shown in Fig.
4A.
L-NAME treatment resulted in a
partial, but significant, reduction of the ACh-induced
endothelium-dependent relaxation, providing further evidence for the
presence of endothelial dysfunction, i.e., inhibition of EDNO
production. Responses to ACh of the aortic rings from the
17-estradiol-treated animals in the presence and absence of
L-NAME administration were not different from the responses of the intact aortic rings from the vehicle-treated control group.
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Endothelium-independent relaxation. Endothelium-independent relaxation to NG was not different between aortic rings isolated from animals in the four treatment groups (Fig. 4B).
Serum Total Cholesterol and Estradiol
Cholesterol feeding resulted in a 20-fold increase of total serum cholesterol. There was no significant difference in the serum total cholesterol level between the four different treatment groups (Table 1).Plasma estradiol was low in the ovariectomized VC group. The
L-NAME-treated ovariectomized
group had similarly low 17-estradiol levels as the control group.
Daily injection with 30 µg 17-estradiol resulted in a significant,
10-fold increase in the circulating estrogen level in both the
E2 and
L-NAME + E2 groups (Table 1).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Diminished endothelium-dependent vasodilation has been demonstrated in both clinical (6) and experimental (5) hypercholesterolemia and atherosclerosis. The impairment in vascular reactivity was largely due to a reduction in EDNO activity and was observed before any detectable morphological changes of atherosclerosis occurred (29). Chronic L-NAME administration to hypercholesterolemic rabbits resulted in significant suppression of basal and stimulated EDNO production with significant acceleration of atherosclerotic plaque development (3, 22), demonstrating the important protective role of EDNO in atherosclerosis. EDNO exerts a wide variety of potentially antiatherogenic effects, such as inhibition of platelet aggregation, leukocyte adhesion, smooth muscle proliferation, and vasoconstriction (11). Improved endothelial function could potentially contribute to the clinical benefit of patients as has been suggested in the case of lipid-lowering agents (26) and angiotensin-converting enzyme inhibitors (21).
Impaired EDNO availability in atherosclerosis can be the result of multiple mechanisms including increased degradation of NO, reduced availability of substrate or cofactor, presence of endogenous inhibitors, or reduced expression of NOS III (4, 11). The heterogeneity of the cause of endothelial dysfunction may limit the therapeutic strategies used in the treatment of atherosclerosis.
Numerous epidemiological evidence supports the role of estrogens in the reduced incidence of coronary heart disease in hormone replacement-treated postmenopausal women (8, 19, 23). Antiatherosclerotic effect of estrogen involves several mechanisms (8, 19, 23), among which the stimulatory effect on EDNO production has been well documented (1, 7, 10, 12-15, 18, 20, 28). Treatment with estrogens resulted in improved endothelium-mediated vasodilation and NO release (1, 10) or increased expression of NOS III, demonstrated both in vivo and in vitro (9, 13, 14, 20, 28).
The role of EDNO in mediating the cardiovascular protection by estrogen
has been suggested based on findings that the antiatherosclerotic effect of 17-estradiol was inhibited by the removal of the
endothelium in atherosclerotic rabbits (16) and that decreased
accumulation of cholesterol into the aortic wall of
hypercholesterolemic rabbits in response to treatment with estrogens
was attenuated by L-NAME treatment (15). However, chronic NOS inhibition by
L-NAME did not influence the
antiatherosclerotic effect of 17-estradiol in apolipoprotein
E-deficient mice (7). This apparent discrepancy between these studies
can be explained by differences in the end points measured to document
the antiatherosclerotic effect of estrogen, the degree of NOS
inhibition achieved, or differences in species. The inhibition of NOS
by L-NAME had no significant effect on the measured end points in these studies, indicating that
lipid accumulation into the aortic wall (15) or the area of
lipid-filled lesions at the level of the aortic valves (7), used to
evaluate the extent of atherosclerosis, may not be sensitive enough to
detect changes due to EDNO inhibition alone. In addition, none of these
studies provided evidence of changes in EDNO-mediated vasorelaxation,
as a measure of NOS function in response to
L-NAME or 17-estradiol
treatment, in the animals in which the effect on atherosclerosis was investigated.
In our study, plaque-to-surface area ratio of the thoracic aorta and the aortic arch was significantly increased in the L-NAME-treated rabbits that exhibited severe endothelial dysfunction. These results are in agreement with earlier findings of others using plaque-to-surface area ratio for the measurement of atherosclerosis (22). Basal EDNO production, which reflects the level of bioavailable EDNO (assessed by L-NNA contraction of endothelium intact isolated aortic rings; Ref. 25), was reduced by ~75% in vessels isolated from the chronic L-NAME-treated group. Stimulated EDNO release by ACh was also significantly suppressed but to a lesser extent than basal EDNO. Thus L-NAME treatment of rabbits caused severe but not complete inhibition of EDNO production under these conditions, similar to that observed in advanced stages of cardiovascular diseases (e.g., atherosclerosis or hypertension) (4, 6, 11, 24). This loss in EDNO production was accompanied by an ~20% increase in plaque-to-surface area ratio. Clinical data also indicate a good correlation between the severity of atherosclerosis and the degree of endothelial dysfunction assessed by impairment in endothelium-dependent vasodilation (11).
In the present study, estrogen treatment resulted in significant
reduction of atherosclerotic lesion development measured by
plaque-to-surface area ratio. The change in lesion area was accompanied
by enhanced basal EDNO-mediated responses, assessed by
L-NNA-induced contraction of
isolated aortic rings. This finding demonstrated that the
antiatherosclerotic effect of 17-estradiol is associated with
increased EDNO formation in the same animal. This observation is in
good agreement with earlier clinical reports that physiological levels
of 17-estradiol potentiate vasodilation in response to
endothelium-dependent vasodilators (10). Lack of endogenous estrogen in
ovariectomized rabbits has been shown previously to lead to suppression
in basal EDNO production without any alteration in ACh-stimulated EDNO
release (12). Our findings that 17-estradiol treatment augmented
basal but not ACh-induced EDNO release are in support of this earlier finding.
Lack of inhibition of the antiatherosclerotic effect by estrogen using
L-NAME may argue against the
dominant role of EDNO in solely mediating cardiovascular protection by
17-estradiol. Similar findings have been reported in apolipoprotein
E-deficient mice (7). However, basal EDNO production was significantly enhanced by 17-estradiol even in the presence of
L-NAME. The percent
increase in basal EDNO by estrogen was not significantly different with
and without L-NAME treatment.
Augmented EDNO formation by estrogen can be achieved by different
mechanisms involving genomic regulation of the NOS III gene itself (13,
14, 20) or by nongenomic pathways via protection of the existing NO
from rapid degradation (1) or short-term improvement of EDNO-mediated vasorelaxation (10). The present study was not designed to analyze the
exact mechanism whereby 17-estradiol treatment resulted in significant increases in EDNO availability under the experimental conditions used. The most likely explanation for the observed increased
EDNO release even in the presence of the NOS inhibitor L-NAME is that 17-estradiol
increased NOS III protein synthesis. However, the possibility of
enhanced substrate and/or cofactor availability in response to
17-estradiol treatment or diminished degradation of NO cannot be
ruled out on the basis of our study.
The present data show a strong inverse relationship between changes in
EDNO production and the extent of vascular lesion development in all
treatment groups, further supporting the earlier finding (15) that the
level of EDNO production is a key determinant of atherosclerotic lesion
progression. Under these experimental conditions, the
antiatherosclerotic effects of 17-estradiol could not be dissociated
from increased EDNO production, suggesting that EDNO may play an
important role in mediating this effect. The contribution of additional
mechanisms to cardiovascular protection (8, 19, 23), including
inhibition of smooth muscle proliferation, suppression of vascular cell
activation, and antioxidant activity, as well as
endothelium-independent vasodilation, should also be considered, which
allowed the significant protection against atherosclerotic plaque
development despite the significant reduction in EDNO production by
L-NAME. The contribution of the
above mechanisms to protection against atherosclerosis may vary
depending on the severity of hypercholesterolemia, vascular bed, or
species. The involvement of these additional beneficial effects could
only be studied under experimental conditions with complete inhibition
of EDNO release and prevention of 17-estradiol-induced increase in
EDNO production.
In summary, the present study demonstrates that 17-estradiol
treatment is efficacious in atherosclerosis even in situations when
EDNO production is severely impaired. Our results indicate a strong
correlation between EDNO production and atherosclerotic lesion
development in this animal model of atherosclerosis. The data indicate
that, in ovariectomized, hypercholesterolemic rabbits, estrogen-evoked
cardiovascular protection is mediated at least in part by increased
EDNO production even in the presence of a NOS inhibitor. The fact that
the antiatherosclerotic effect of 17-estradiol persisted after
significant impairment of endothelial function by
L-NAME suggests that estrogen
therapy may exert cardiovascular benefits even in patients with severe
endothelial dysfunction, possibly by increasing the expression of NOS
III protein.
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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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: K. Kauser, Berlex Biosciences, Cardiovascular Department, 15049 San Pablo Ave., Richmond, CA 94804-0099 (E-mail: Katalin_Kauser{at}Berlex.com).
Received 23 July 1998; accepted in final form 20 January 1999.
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TOP
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METHODS
RESULTS
DISCUSSION
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