(Circulation. 2000;101:94.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
17ß-Estradiol Restores Endothelial Nitric Oxide Release to Shear Stress in Arterioles of Male Hypertensive Rats
From the Department of Physiology, New York Medical College, Valhalla.
Correspondence to An Huang, MD, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail an huang{at}nymc.edu
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Abstract |
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Background—Endothelial nitric oxide (NO)–mediated responses are impaired in arterioles of male spontaneously hypertensive rats (SHR), but they are still present in female SHR. We hypothesized that in vitro incubation of arterioles of male SHR with estrogen will restore NO-mediated responses by upregulation of endothelial NO synthase.
Methods and Results—Responses to increases in perfusate
flow (from 0 to 25 µL/min) and to the calcium ionophore A23187
(5x10-8 to 10-6 mol/L),
norepinephrine (NE; 10-7 to
3x10-7 mol/L), sodium nitroprusside (SNP;
10-8 to 10-6 mol/L), and adenosine
(ADO; 10-6 to 5x10-5 mol/L) were studied in
cannulated and pressurized gracilis muscle arterioles (
75 µm
in diameter) isolated from 12-week-old male SHR before and after
incubation with 10-9 mol/L 17ß-estradiol
(17ß-E2) for 16 to 18 hours. After incubation with
17ß-E2, basal diameter of arterioles was significantly
increased (by 10%), and flow-induced dilation was significantly
enhanced (79.8±2.9 versus 103.7±3.7 µm at 25 µL/min),
resulting in a lowered shear stress (62.0±9.1 versus 32.5±4.2
dyne/cm2). Also, vasoconstrictions to A23187 were reversed
to dilations (-18.7±2.2 versus 18.8±1.7 µm), and
constrictions to NE were significantly attenuated (-30.7±3.0 versus
-21.2±2.8 µm). These alterations were eliminated by ICI
182,780 (10-7 mol/L), an estrogen receptor
antagonist;
5,6-dichloro-1-ß-D-ribofuranosylbenzimidazole
(10-5 mol/L), a transcription inhibitor; or
N
-nitro-L-arginine methyl
ester (10-4 mol/L), an inhibitor of NO
synthase, whereas they were not affected by aminoguanidine
(5x10-5 mol/L), a specific inhibitor of
inducible NO synthase. Arteriolar responses were not altered by
incubation with 17
-estradiol.
Conclusions—Estrogen, via a receptor-mediated pathway, upregulates endothelial NO synthase gene expression, leading to increased NO production, and restores the regulation of wall shear stress in arterioles of male SHR.
Key Words: endothelium • vasodilation • hormones • receptors
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Introduction |
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Recent studies documented that estrogen contributes to the sex difference in the incidence of cardiovascular diseases.1 These studies also suggested several mechanisms by which estrogen could evoke its beneficial cardiovascular effects. Increasing evidence suggests that upregulation of endothelial nitric oxide synthesis by the long-term presence of estrogen is one such possible mechanism.1 The greater NO-mediated vascular responses in female normotensive2 as well as hypertensive animals compared with their male counterparts indicates that estrogen potentiates endothelial function.3 Estrogen replacement therapy significantly enhanced the acetylcholine-induced NO-mediated relaxation of the aorta of gonadectomized male spontaneously hypertensive rats (SHR).4 Also, long-term treatment of cholesterol-fed rabbits with estrogen decreased atherosclerotic lesions significantly, which was paralleled by an improved NO-dependent endothelial function.5 Moreover, estrogen replacement restored basal NO release in ovariectomized female rats with chronic heart failure.6 In humans, a link between the plasma levels of estrogen and NO in perimenopausal and postmenopausal women7 8 was also demonstrated, whereas in preeclampsia with hypertension, a lower circulating estrogen level is associated with reduced release of NO.9 Thus, a positive relationship between estrogen and basal or stimulated release of NO has been established in both large and small vessels, in vivo and in vitro.10 14
One of the important local factors participating in the regulation of arteriolar tone is wall shear stress, which is the primary stimulus for the release of endothelial NO.15 16 An impaired dilation in response to increases in shear stress could play an important role in the increased arteriolar resistance in hypertension.9 17 Our previous studies demonstrated that NO-mediated dilations to agonists18 19 and flow/shear stress20 21 are impaired in arterioles of male SHR. In contrast, in female SHR, arteriolar release of NO is still, in large part, preserved.19 22
The mechanism by which the long-term presence of estrogen in vivo improves endothelial function, as manifested by enhanced NO-mediated responses, is not yet identified. It remains of interest, therefore, to elucidate whether and to what extent these responses are a result of greater release of NO elicited by estrogen-induced upregulation of NO synthase or of other mechanisms, including the effects of estrogen on plasma lipid profile.23 To exclude these possible in vivo effects of estrogen, we designed in vitro studies. We hypothesized that incubation of arterioles of male SHR with estrogen can restore NO-dependent responses. Thus, we conducted experiments in isolated cannulated and pressurized arterioles that were incubated with physiological concentrations of estrogen to reveal the direct effects of estrogen on endothelium-dependent, NO-mediated responses.
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Methods |
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Experimental Setup
Experiments were conducted on single arterioles (
75 µm
in diameter) of gracilis muscle isolated from 12-week-old male SHR.
Rats were anesthetized with an injection of sodium
pentobarbital 50 mg/kg IP. The dissection and isolation procedure of
arterioles has been described previously.13 An 1-mm
segment of an arteriole was isolated and cannulated with 2 glass
pipettes in a vessel chamber and suffused (1 mL/min) with sterilized
physiological salt solution containing
10-5 mol/L L-arginine and 1%
antibiotic-antimycotic (Gibco Laboratory) buffered with
NaHCO3 (24.0 mmol/L)/5%
CO2 plus ambient air to maintain pH at 7.4. The
vessel chamber consisted of 2 parallel chambers that were perfused
separately. Intravascular pressure and temperature were maintained at
80 mm Hg and 37°C, respectively. Intraluminal flow was
established by changing proximal and distal pressures, controlled by 2
pressure-servo systems (Living Systems Inc), to an equal degree but in
opposite directions without changing intravascular
pressure.16 The flow rate was measured by a microflowmeter
(FL-300, Omega).
Method of Incubation
After control experiments, isolated arterioles were incubated
with 17ß-estradiol (17ß-E2,
10-9 mol/L) in a cannulated, pressurized
(50 mm Hg), and perfused condition at 37°C for 16 to 18 hours.
The double-pipette chamber allows incubation of 2 vessels
simultaneously, but independently, with, eg,
17ß-E2 and 17ß-E2 plus
ICI 182,780, a specific estrogen receptor
antagonist.24
Experimental Protocols
Changes in diameter of arterioles in response to increases in
perfusate flow or to agonists were assessed. Vessels were
equilibrated at 80 mm Hg of perfusion pressure without flow for 1
hour to develop spontaneous tone. Then perfusate flow was
increased from 0 to 25 µL/min in 5-µL/min steps. After the
flow-diameter relationships were obtained, flow was stopped, and then
responses to the calcium ionophore A23187
(5x10-8 to 10-6
mol/L), norepinephrine (NE, 10-7 to
3x10-7 mol/L), sodium nitroprusside (SNP,
10-8 to 10-6 mol/L), and
adenosine (ADO, 10-6 to
5x10-5 mol/L) were tested at 80 mm Hg
perfusion pressure.
In the first protocol, arteriolar responses to flow and agonists were
assessed in control and after incubation with
17ß-E2 10-9 mol/L (see
Method of Incubation). On the basis of our preliminary experiments,
this concentration of estrogen has no direct effect on the vascular
diameter. After the incubation period, the vessel was reequilibrated at
80 mm Hg for 1 hour, and agonist- and flow-induced responses were
reassessed. In the second protocol, after incubation with
17ß-E2, the endothelium was
removed to test whether the estrogen-related alteration in responses is
endothelium-dependent. In the third protocol, the
magnitude of NO-mediated responses was assessed with
N-nitro-L-arginine
methyl ester (L-NAME, 10-4 mol/L), an
inhibitor of NO synthase. After incubation with
17ß-E2, L-NAME was administered for an
additional 20 minutes before the experiment was repeated. In the fourth
protocol, the role of estrogen receptors in the responses was tested by
incubation of the vessel with 17ß-E2 plus ICI
182,780 (10-7 mol/L), an inhibitor
of estrogen receptors.24 In the fifth protocol,
vessels were incubated with 17ß-E2 in the
presence of 5,6-dichloro-1-ß-D-ribofuranosylbenzimidazole
(DRB, 10-5 mol/L), a reversible RNA polymerase
II inhibitor, to clarify the nature of the genomic
response.25 Next, we used 17-E2
10-9 mol/L for incubation of the vessels to
exclude nonspecific steroid effects. The possible involvement of
inducible nitric oxide synthase (iNOS) in these responses was also
studied with aminoguanidine 5x10-5 mol/L to
inhibit iNOS.26 27 17ß-E2–incubated vessels
were subjected to aminoguanidine for 20 minutes before the
experiments.
At the conclusion of each experiment, the suffusate solution was changed to a Ca2+-free physiological salt solution with EGTA (1.0 mmol/L). The vessels were incubated for 10 minutes, and the passive diameter of arterioles was obtained at 80 mm Hg. ICI 182,780 was a gift from Zeneca Pharmaceutical, England. All other drugs were obtained from Sigma Chemical Co. Estrogens and A23187 were dissolved in DMSO and then diluted with distilled water. The highest concentration of DMSO in the chamber was 0.1% (vol/vol), which had no effect on vascular tone.
Statistics
Data are presented as mean±SEM. Flow-induced responses
were normalized to the passive diameters and expressed as percent
change. Wall shear stress was calculated by the equation
4
Q/
r3, where is the viscosity of the
perfusate (0.007 poise at 37°C), Q is the perfusate
flow, and r is the vessel radius. Responses to agonists were expressed
as change in diameter. Statistical analyses were done by 2-way
ANOVA, followed by Tukey’s post hoc test. A value of
P<0.05 was considered significant.
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Results |
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The active diameters of arterioles in control and after incubation with 17ß-E2 were significantly different (72.8±3.3 and 79.8±2.9 µm, respectively). The passive diameter of arterioles was 136.5±4.1 µm. The arteriolar tone, expressed as percent of passive diameter, was also significantly different before and after incubation with 17ß-E2 (52.9±1.3% versus 58.3±0.8%).
Figure 1
(top) shows the normalized
diameter of arterioles in response to increases in perfusate
flow in control conditions and after 16 to 18 hours of incubation with
17ß-E2. In control conditions, increases in
flow (from 0 to 25 µL/min) elicited increases in the diameter. After
incubation with 17ß-E2, arteriolar dilations to
flow were significantly enhanced at all flow rates (eg, by 89%
increase at maximal flow rate; 79.8±2.9 versus 103.7±3.7 µm).
Also, the significant difference in the slope of flow-diameter curves
indicates that after 17ß-E2 incubation,
arterioles of male SHR dilated significantly more to increases in flow.
Calculated wall shear stress (bottom) indicates that the shear stress
values were significantly higher in control conditions (maximum,
62±9.1 dyne/cm2) than after
17ß-E2 incubation (maximum, 32.5±4.2
dyne/cm2). To test the role of the
endothelium in the
17ß-E2–induced alteration, the
endothelium was removed after incubation. In this
condition, flow-induced dilation was completely eliminated (Figure 2, top), confirming our hypothesis that
the restored flow-induced dilation by 17ß-E2
incubation is endothelium-dependent. Next, we
investigated the roles of both endothelial NOS (eNOS) and iNOS
in the restored flow-induced dilation by incubation with
17ß-E2. Figure 2 (middle) shows that
L-NAME abolished the estrogen-induced improvement of NO mediation,
whereas it was not affected by aminoguanidine (bottom), indicating that
the improved flow-induced dilation is mediated by NO derived from
eNOS.
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To ascertain further that incubation with estrogen restores NO
mediation, arteriolar responses to A23187, NE, SNP, and ADO were
investigated (Figure 3). In control
conditions, A23187 elicited constriction of arterioles from male SHR,
as we found previously.18 This was converted to dilation
after incubation with 17ß-E2, which also
significantly attenuated constrictions to NE. Dilations to SNP,
however, were reduced by incubation with
17ß-E2. Administration of L-NAME after
17ß-E2 incubation not only prevented the
dilations but also, compared with control, increased constrictor
responses to A23187 as well as to NE. Dilator responses to SNP were
affected only at the highest concentration. Arteriolar responses to ADO
were not affected in any of the conditions studied.
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The nonspecific steroid action of estrogen on improved flow-dependent
dilation was excluded by the findings that responses of vessels
incubated with 17-E2 were not different from
control (Figure 4, top). To further
determine whether estrogen receptors and gene transcription are
required for the effects of 17ß-E2, in separate
experiments, the action of 17ß-E2 was assessed
by use of ICI 182,780 and DRB to block estrogen receptors and gene
transcription, respectively. As shown in Figure 4, ICI 182,780
(middle) or DRB (bottom), incubated together with
17ß-E2, prevented the restoration of
flow-induced dilation, suggesting that hormone receptors and gene
transcription are required for the action of estrogen. Figure 5 shows the effects of DRB on control
responses of arterioles to flow (top) and agonists (middle and bottom).
The maintained arteriolar responses indicate that control responses
were not significantly affected by 16 to 18 hours of DRB treatment.
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Discussion |
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The salient findings of the present study are that incubation of skeletal muscle arterioles isolated from male SHR with physiological concentrations of 17ß-E2 for 16 to 18 hours restored NO-mediated flow- and agonist-induced dilations. Furthermore, transcriptional upregulation of eNOS, mediated by estrogen receptors, is responsible for the observed changes.
Previous studies demonstrated that estrogen replacement therapy increases blood flow to various tissues by mechanisms that involve an enhanced synthesis of endothelial NO.2 28 29 In vivo, an important stimulus for the release of NO is an increase in wall shear stress elicited by increases in perfusate flow.15 16 Previously, we found a sex difference in responses to flow/shear stress of rat arterioles due to an enhanced NO synthesis/activity, which was dependent on the presence of estrogen in females.14 22 It is likely that multiple mechanisms are involved in the estrogen-related potentiation of NO-mediated vascular responses in vivo. It was also reported that inhibition of superoxide production by estrogen results in an increased activity of NO without an enhancement of the gene expression and level of NOS protein.30 Thus, it was of interest to better define the nature of the mechanism(s) by which estrogen affects NO release in the absence of other mechanisms that may also play a role in the estrogen-related vascular effects in vivo. Isolated arterioles of gracilis muscle of male SHR were chosen for the present study because previous studies demonstrated that the NO-mediated portion of flow-induced response is impaired in these vessels.20 21
We hypothesized that the impaired NO-mediated flow-induced responses in skeletal muscle arterioles of male SHR could be normalized by incubation of vessels with 17ß-E2 via transcriptional upregulation of NO synthase. To the best of our knowledge, this is the first demonstration that a physiological concentration of estrogen in vitro can alter the reactivity of resistance vessels to shear stress and vasoactive agents.
Attenuated Arteriolar Tone After 17ß-E2
Incubation
The basal tone of arterioles was different in control conditions
and after incubation with 17ß-E2 (Figure 1
). The difference in arteriolar tone after
17ß-E2 incubation was eliminated by removal of
the endothelium or inhibition of NO synthesis by L-NAME
(Figure 2, top and middle), suggesting that a greater basal
release of endothelial NO accounts for the reduced
myogenic tone of arterioles incubated with estrogen. This finding
agrees with previous studies of the effects of the in vivo presence of
estrogen.6 8 13 19
Restored NO-Mediated Responses to Flow/Shear Stress and Agonists
After Incubation With 17ß-E2
Arterioles that had been exposed to 17ß-E2
overnight exhibited a significantly augmented dilation in response to
increases in flow compared with control responses, as shown by the
significant leftward shift in the slope of the flow-diameter curves
(Figure 1, top). These responses were not altered by incubation
with 17-E2 (Figure 4, top), indicating
a specific action of 17ß-E2 on the vascular
function. The physiological relevance of the
enhanced flow-induced dilation is indicated further by the calculation
of wall shear stress (Figure 1, bottom). It shows a significant
leftward shift of the shear stress–diameter curve after incubation
with 17ß-E2, revealing that the value of shear
stress required to dilate arterioles maximally is significantly less
than in control. These findings support the idea that in hypertension,
impairment of the regulation of shear stress in arterioles, because of
a lesser release of endothelial NO, may contribute to
the elevated peripheral resistance.9 17
Furthermore, because incubation with 17ß-E2
restores the capacity of the endothelium to regulate
shear stress, this mechanism may be responsible, at least in part, for
the delayed onset and/or less severe development of hypertension in
females.
Our previous studies showed that flow-dependent dilation of gracilis
muscle arterioles, vessels that were also used in the present
study, is mediated by endothelial NO and
prostaglandins16 and that in male SHR, the
NO-mediated portion of the response is absent.20 21 In
arterioles of female SHR, however, NO-mediated flow-induced dilation is
retained.22 To elucidate the endothelial
nature of the improved flow-induced dilation after
17ß-E2 incubation, the
endothelium was removed and the effect of L-NAME on the
responses was investigated (Figure 2).
Endothelium-denuded arterioles did not dilate to
increases in flow (Figure 2, top) after exposure to
17ß-E2. Also, L-NAME abolished the enhanced
portion of the flow-induced response elicited by incubation with
17ß-E2 (Figure 2, middle), indicating
that incubation with 17ß-E2 normalizes the
impaired NO-mediated flow-induced dilation.
Recent studies showed that incubation of
endothelium-denuded rat aortas with
17ß-E2 reduced vasoconstriction to
phenylephrine via an upregulation of iNOS.26
To assess the possible involvement of iNOS in the
17ß-E2 incubation-related responses,
aminoguanidine 5x10-5 mol/L was administered to
vessels after incubation with 17ß-E2. The
concentration of aminoguanidine used inhibits iNOS-induced citrulline
formation by 90% and nitrite formation by 60%, without
significantly interfering with eNOS activity and the basal release of
NO.27 Figure 2 (bottom) shows that administration
of aminoguanidine did not affect the flow-diameter curve of vessels
incubated with 17ß-E2, indicating that iNOS is
unlikely to have been involved in the enhanced responses to flow.
The effect of 17ß-E2 incubation on arteriolar
responses to vasoactive agents (Figure 3) adds further evidence
to the restoration of NO synthesis by 17ß-E2.
Previously, as in the present study, we found that hypertension not
only impairs NO synthesis in arterioles of male SHR but also diverts
prostaglandin synthesis from dilator to constrictor
prostanoids (PGH2), resulting in an
endothelium-dependent constriction to
A23187.18 After incubation of arterioles with
17ß-E2, the dilation to A23187 is restored in
an L-NAME–reversible manner, suggesting that increased
production of NO after incubation with
17ß-E2 outweighs the effect or prevents the
production of PGH2 in response to A23187.
The attenuated constriction to NE after 17ß-E2
incubation was eliminated by the presence of L-NAME, indicating a
greater concomitant release of NO by estrogen. Dilator responses to SNP
were significantly reduced after in vitro exposure to estrogen but were
partially reversed by simultaneous administration of
L-NAME. On the basis of previous findings,31 32 we
speculate that a greater tonic release of NO due to incubation with
estrogen lowers the sensitivity of vessels to nitrovasodilators.
Although the mechanism for this remains unclear, a possible explanation
may be related to a downregulation of guanylate cyclase or
the cGMP-dependent protein kinase.
Mechanisms Responsible for the Restored NO-Mediated Responses by
Incubation With 17ß-E2
Estrogen-related enhanced NO mediation of vascular responses could
be due to an altered transcriptional (genomic) and posttranscriptional
regulation, cofactor or substrate availability, nongenomic effects, or
other, as yet unidentified, factors.1 Estrogen receptors
have been identified to be present in endothelial
cells,33 and genomic regulation of
endothelial function by estrogen has been shown to be
estrogen receptor–dependent.1 33 34 Activation of
estrogen receptors affects an estrogen response element on the promoter
of certain genes (such as eNOS) to initiate target gene
expression.35 We speculated that the restoration of the
NO-mediated flow-induced response by 17ß-E2
incubation is due to an upregulation of eNOS gene expression, followed
by increased eNOS activity, providing for a greater NO release in
response to increases in shear stress as well as vasoactive agents. To
test this hypothesis, the vessels were incubated with
17ß-E2 in the presence of ICI 182,780. We found
that blockade of estrogen receptors prevented the restoration of
NO-mediated dilations elicited by 17ß-E2
(Figure 4, middle), suggesting that estrogen receptors play a
crucial role in the responses. The presence of the transcription
inhibitor DRB prevented the restoration of responses to
estrogen (Figure 4, bottom), suggesting that the effect of
17ß-E2 in the present study is primarily
transcriptionally based. DRB, in a concentration of
10-5 mol/L, effectively inhibited the augmented
(NO-mediated) portion of the responses after
17ß-E2 incubation (Figure 4, bottom) yet
did not affect the responses in control conditions (Figure 5).
Thus, the experiments with ICI 182,780 and DRB suggest that the
estrogen-related restoration of NO release to shear stress in
arterioles of male SHR is a genomic effect, mediated via estrogen
receptors. Moreover, the finding that 17ß-E2
incubation improves NO mediation of vascular responses, regardless of
whether NO release is elicited by shear stress or vasoactive agents,
provides a convincing argument that
17ß-E2–induced transcriptional upregulation of
eNOS accounts for the observed restoration of NO-mediated responses.
Our conclusion is congruent with studies showing that estrogen
upregulates eNOS gene expression in cultured
endothelial cells34 and that there is
significantly reduced basal release of NO in aorta of estrogen receptor
knockout mice.36
Recently, a new mechanism regarding an acute estrogen-induced activation of eNOS has been reported. This activation is mediated by estrogen receptors but is nongenomic in nature, as indicated by the failure of actinomycin D or DRB to prevent the effect of estrogen.37 38 The potential mechanism causing the alteration is reported to be either dependent on37 or independent of38 cytosolic Ca2+, revealing a species- or tissue-specific response to estrogen.
In summary, we found that incubation with physiological concentrations of estrogen normalizes the impaired dilator responses of skeletal muscle arterioles of male hypertensive rats to shear stress and vasoactive agents by an estrogen receptor–mediated, transcriptional upregulation of eNOS. The results may well form the basis of the mechanism by which estrogen protects against vascular injury and exerts its beneficial effect on the cardiovascular system.
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Acknowledgments |
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This study was supported by AHA grant 9930244N (Dr Huang), AHA NY State affiliate grant 9830015T (Dr Sun), and NIH grants HL-46813 (Dr Koller) and HL-43023 (Dr Kaley). We gratefully acknowledge the generous supply of ICI 182,780 from Dr A.E. Wakeling, Zeneca Pharmaceutical.
Received February 25, 1999; revision received July 7, 1999; accepted July 15, 1999.
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