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Department of Physiology, New York Medical College, Valhalla, New York 10595
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ABSTRACT |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Previous studies show that
agonist-induced, nitric oxide (NO)-mediated arteriolar dilations are
greater in female than in male rats. Thus we hypothesized that
flow-dependent arteriolar dilation, which is in part mediated by NO, is
also greater in females than in males. Gracilis muscle arterioles from
12-wk-old female and male Wistar rats were isolated, cannulated, and
pressurized. At 80 mmHg of perfusion pressure, the active diameter and
passive diameter (PD) of arterioles of female and male rats were 58.3 ± 3.4 and 53.2 ± 2.6 µm as well as 103.6 ± 4.0 and 115.3 ± 4.8 µm, respectively. Dilations to step increases in
perfusate flow from 0 to 25 µl/min were significantly greater in
arterioles of female rats and ovariectomized rats with estrogen
replacement (OVE) than in male and ovariectomized female (OV) rats
(98.6 ± 0.6 and 97.4 ± 1.1% vs. 72.6 ± 3.3 and 72.5 ± 3.6% of PD at 25 µl/min). Calculation of wall shear stress (WSS)
revealed that the maintained WSS was significantly lower in arterioles
of female than in those of male rats (~20 vs. ~35
dyn/cm2). After indomethacin
pretreatment,
N
-nitro-L-arginine
methyl ester (L-NAME;
10
4 M) eliminated
flow-dependent dilation in arterioles of male and OV rats but only
attenuated (by ~50%) the responses in arterioles of female and OVE
rats. In vessels of these latter two groups of rats, the remaining
flow-induced dilation was completely eliminated by administration of
105 M Hb or
103 M
L-NAME. The greater flow/shear
stress-induced dilation of arterioles of female rats indicates a gender
difference in the regulation of WSS, which is likely to be due to the
greater release of NO in female vessels requiring the chronic presence
of estrogen. These findings suggest an important role for estrogen in
the regulation of peripheral resistance in females.
microvessels; arterioles; endothelium; peripheral resistance
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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POPULATION-BASED STUDIES suggest that before menopause
women have a delayed and less severe manifestation of cardiovascular diseases than men (1, 7). This observation prompted numerous investigations to analyze the differences between the regulation of the
cardiovascular system of females and males to elucidate the causes for
the observed gender differences. One possible cause is that the
regulation of peripheral vascular resistance is different in females
and males. It was found that estrogen replacement therapy in
postmenopausal women increases blood flow in the aorta (12) and in
cerebral (11) and uterine (18) vessels. It was also shown that estrogen
increases coronary blood flow and dilates epicardial coronary arteries
in humans (2). Furthermore, acute sublingual administration of
17
-estradiol significantly increased blood flow in forearm vessels
in postmenopausal women (16), and intracoronary injection of
17-estradiol in physiological concentrations enhanced
acetylcholine-stimulated increases in coronary blood flow (15) and
attenuated acetylcholine-induced constriction in coronary conduit
arteries in postmenopausal women (14). Collectively, these studies
indicate that both large vessels and microvessels are affected by the
acute or chronic presence of estrogen in plasma. The possible
underlying mechanisms for the acute effects of estrogen are still not
elucidated, but a role for the endothelium in the long-term effects of
estrogen has been suggested by several clinical and experimental
studies (1, 3, 5, 10).
Previously, we have found a significantly greater dilation to substance P and an attenuated pressure-induced myogenic constriction in isolated arterioles of skeletal muscle of female compared with those of male rats, responses that are dependent on the greater release of nitric oxide (6), whereas the dilator effects of a nitric oxide donor were not different. In accordance with these observations, an increased expression of endothelial nitric oxide synthase by the chronic presence of estrogen has been documented (4, 17).
In vivo, an increase in flow/wall shear stress is perhaps the most effective stimulus for the release of nitric oxide (8, 9). There are as yet no studies extant that examined the possible effects of estrogen on endothelial regulation of shear stress, which would be especially important in microvessels in which increases in shear stress have already been shown to elicit great increases in diameter through nitric oxide release (8, 9). In this context, the significant increase in blood pressure elicited by systemic inhibition of nitric oxide synthase (13), in part, is likely to be caused by the lack of shear stress-induced release of nitric oxide in the peripheral circulation.
On the basis of the aforementioned, we hypothesized that the flow/shear stress-induced dilation of skeletal muscle arterioles is greater in females than in males and that this is because of the greater release of nitric oxide, for which the chronic presence of estrogen is necessary. To test this idea, arterioles of gracilis muscle of male and female rats, including ovariectomized rats (OV) and ovariectomized rats with estrogen replacement (OVE), were isolated and cannulated, and changes in diameter, as a function of perfusate flow/shear stress, were contrasted.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Experimental animals.
Twelve-week-old Wistar rats (Charles River Laboratories, Wilmington,
MA) were divided into four groups: male, female, OV, and OVE.
Ovariectomy was performed at 9 wk of age (6). Rats were anesthetized by
inhaling methoxyflurane (Metofane). An incision of ~1 cm in length
was made on both sides of the back to expose the ovaries
retroperitoneally. Ovaries were removed by clamping and cutting between
them and the uterus; the Fallopian tubes were then ligated, and the
skin was closed with sutures. One week after the operation, rats were
divided into two groups. One group received injection of
17-estradiol benzoate (50 µg/kg, every 48 h) in sesame oil
subcutaneously for 3 wk, and the other group received the vehicle only.
The volume of each injection was 0.1 ml. The 17-estradiol benzoate
was dissolved in pure ethanol (5 mg/ml) with sesame oil as vehicle.
Isolation of arterioles. Experiments were conducted on isolated arterioles (~55 µm ID) of rat gracilis muscle. Rats were anesthetized with an intraperitoneal injection of pentobarbital sodium (Nembutal, 50 mg/kg). The isolation procedure of arterioles has been described previously (8). Briefly, the muscle was excised and placed into a refrigerated dissecting dish containing a cold (0-4°C) modified physiological salt (PS1) solution. The PS1 solution contained (in mM) 145 NaCl, 5 KCl, 2.0 CaCl2, 1.0 MgSO4, 1.0 NaH2PO4, 5.0 dextrose, 2 pyruvate, 0.02 EDTA, and 3.0 MOPS to reach pH 7.4. The muscle was splayed open as a flat sheet of tissue and pinned to the bottom of the silicone-lined base of a Petri dish. Rats were killed by an overdose of pentobarbital sodium injected into the abdominal aorta. With microsurgery instruments and an operating microscope (Leica, Thornwood, NY), we isolated a ~1-mm-long segment of an arteriole from the gracilis muscle and surrounding tissue and transferred it to the vessel chamber. The chamber contained a pair of glass micropipettes filled with a second physiological salt (PS2) solution at room temperature. The PS2 solution used for suffusion and perfusion of the vessels contained (in mM) 118 NaCl, 5 KCl, 2.5 CaCl2, 1.0 MgSO4, 1.0 KH2PO4, 24 NaHCO3, 10 dextrose, and 0.02 EDTA and was equilibrated with a gas mixture of 21% O2, 5% CO2, and balanced with N2, at pH 7.4 (37°C). From a reservoir (50 ml), the vessel chamber (15 ml) was continuously supplied via tubing (35 ml) with PS2 solution at a rate of 40 ml/min. After the vessel was mounted on the proximal pipette and secured with sutures, the perfusion pressure was raised to 20 mmHg to clear the clotted blood from the lumen, and the other end of the vessel was mounted on the distal pipette. To flush the vessel and cannulas, the system was perfused for several minutes. The perfusion pressure was then slowly (~1 min) increased to 80 mmHg. At this time, the pressure-servo system was placed in manual mode in which the stable pressure value indicated that there was no leak in the system. The pressure-servo system was then set in the automatic mode at 80 mmHg, and the vessel was allowed to equilibrate for ~1 h.
Perfusion system. As described previously (6), both the proximal (inflow) and distal (outflow) glass micropipettes in the vessel chamber were connected with silicone tubing to a pressure-servo syringe system (Living Systems, Burlington, VT). The system was arranged to have mirror symmetry; thus the axis of symmetry was located perpendicularly at the middle of the arteriolar segment. Pipettes with similar dimensions and equivalent resistances to flow were used, as assessed by the changes in perfusion pressure in response to increments of flow by a Harvard perfusion pump. This arrangement resulted in equal resistances of the two sides of the system (from the pressure transducer to the tip of the pipette). Perfusate flow was established by changing proximal and distal pressures to an equal degree, but in opposite directions, to keep midpoint luminal pressure constant. The flow was measured by a ball flowmeter (FL-300, Omega, Stamford, CT) calibrated by a Harvard perfusion pump in a flow range of 0-100 µl/min.
Experimental procedure. In all protocols, the changes in diameter of arterioles in response to increases in perfusate flow and agonists were measured. Vessels were equilibrated at 80 mmHg perfusion pressure for 1 h, in a no-flow condition, to develop a steady-state spontaneous tone, then perfusate flow was started and increased from 0 to 25 µl/min in 5-µl/min steps. Each flow step was maintained for 5 min to allow the vessels to reach stable diameter.
The role of nitric oxide in the arteriolar responses to increases in perfusate flow was assessed by the use of N-nitro-L-arginine
methyl ester (L-NAME;
104 M), an inhibitor of
nitric oxide synthase, in the presence of indomethacin
(105 M; control) to exclude
the effects of prostaglandins. After the control flow-diameter curve
was obtained, the vessel was exposed to
L-NAME for 20 min. Then, changes
in diameter in response to increases in perfusate flow were reassessed.
After that, Hb (105 M) was
administered, and the experimental protocols were repeated. In separate
experiments, after control responses, the effect of 103 M
L-NAME was tested. To confirm
the specific effect of inhibitors on flow-dependent responses, time
control experiments were performed by assessing flow-dependent
responses in the absence of inhibitors. Stable responses indicated that
there was no time-related decline in arteriolar responsiveness to flow
during the experiments (data not shown).
All drugs were added to the reservoir connected to the vessel chamber,
and final concentrations are reported. To assess the active tone
generated by arterioles in response to intravascular pressure, at the
conclusion of each experiment the suffusion solution was changed to a
Ca2+-free PS2 solution containing
sodium nitroprusside (104
M) and EGTA (1.0 mM). The vessels were incubated for 10 min, then the
passive diameter of arterioles at 80 mmHg perfusion pressure was
measured.
Salts and chemicals were obtained from Sigma (St. Louis, MO).
L-NAME was obtained from Aldrich
Chemical (Milwaukee, WI). Indomethacin was prepared in sodium carbonate
(25 mM) at a concentration of 5 mg/ml. Bovine Hb was prepared by
dissolving 645 mg Hb and 174 mg sodium dithionite
(Na2S2O4)
in 10 ml sodium phosphate buffer (pH 7.4) saturated with 100%
N2. Sodium dithionite was then
removed by dialysis twice against 4 liters phosphate buffer at 4°C
for 4 h each. The prepared Hb was frozen in aliquots at 
80°C
and used within 2 wk. All other drugs were dissolved in distilled water. After the muscle had been dissected, 5 ml of blood was withdrawn
from the abdominal aorta with a 10-ml syringe containing 0.1 ml heparin
sodium (1,000 U/ml). The blood sample was centrifuged immediately
(3,000 rpm at 4°C for 30 min) to obtain the plasma, kept at
80°C, to measure later the concentration of estradiol. This
was done by RIA with a double-antibody estradiol kit (Diagnostic Products, Los Angeles, CA). The minimal detectable concentration by
this assay is <2 pg/ml. Samples were assayed in duplicate, and means
are reported.
The data reported are means ± SE. Only one vessel was studied from
each animal. Flow-induced responses were expressed as change in
diameter. Wall shear stress was calculated by the following formula:
4
Q/r3, where
is the viscosity of the perfusate (0.007 P at 37°C), Q is the
perfusate flow, and r is the vessel
radius. The value of shear stress required to dilate arterioles
maximally was also calculated. Statistical analyses were done by ANOVA,
followed by Tukey's post hoc test and regression analysis. A
P value of <0.05 was considered
significant.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Animals. Table 1 shows the changes in body weight, uterus weight, and uterus weight-to-body weight ratio in three groups of female rats. The uterus weight of OV females was significantly lower than that of normal females or OVE females (P < 0.01). In contrast, the body weight of OV females was significantly greater than that of normal females or OVE females (P < 0.05). As a result, uterus weight-to-body weight ratio was significantly less in OV females than in normal females or OVE females (P < 0.01). Also shown is the concentration of estradiol in male, normal female, OV female, and OVE female rats. The concentration of estradiol in males or OV females was significantly lower than in normal females or OVE females (P < 0.05), whereas in normal females and OVE females it was comparable.
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Pressure-induced arteriolar tone.
The active, passive, and normalized diameters (expressed as the percent
of passive diameter) of arterioles of males, females, OV females, and
OVE females obtained in the presence of constant intravascular pressure
(80 mmHg, with no perfusate flow) are summarized in Table
2. Normalized diameters in males and OV
females were significantly less compared with those of females and OVE
females, indicating that the pressure-induced basal tone of arterioles of males and OV females is significantly greater than that of females
and OVE females (P < 0.05). Addition
of L-NAME
(104 M) with or without Hb
(105 M) or L-NAME
(103 M) into the chamber
solution (in the presence of indomethacin) significantly reduced both
the basal and normalized diameters of arterioles of females and OVE
females, indicating that inhibition of nitric oxide synthesis elicits
significantly greater changes in diameter of vessels isolated from
females and OVE females than in those from males and OV females.
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Flow-induced responses. Summary data of the changes in diameter of arterioles of four groups of rats in response to step increases in perfusate flow in control conditions (without indomethacin) are depicted in Fig. 1. From 5 µl/min perfusate flow, the diameters of arterioles of females and OVE females started to deviate significantly from those of males and OV females, and at 25 µl/min flow, they were ~28% greater than those of males or OV females. Analyzing the slopes (see Fig. 1) of the flow-diameter curves revealed a significant difference between groups, those with and without estrogen. These results indicate that arterioles of female and OVE female rats dilate to a greater extent in response to step increases in perfusate flow than arterioles of male and OV female rats, a function that correlates with the level of estrogen in plasma.
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Calculated wall shear stress vs. diameter. From the flow and diameter data obtained, wall shear stress was calculated and plotted against the changes in arteriolar diameter. Figure 2 shows that after reaching a threshold value (~18-20 dyn/cm2), a given step increase in wall shear stress elicits a significantly greater increase in diameter of arterioles of female and OVE female rats compared with those of male and OV female rats. This results in a significant leftward shift of the upward portion of the shear stress-diameter curve of female and OVE female arterioles, revealing that the maintained arteriolar shear stress values are ~35 dyn/cm2 in males and ~45 dyn/cm2 in OV females, whereas they are ~20 dyn/cm2 in females and OVE females. Comparison of the shear stress required to dilate arterioles maximally indicates that this value is significantly less in arterioles of females (28.4 ± 3.3 dyn/cm2) and OVE females (27.2 ± 5.1 dyn/cm2) than in those of male (44.2 ± 5.3 dyn/cm2) and OV female rats (69.9 ± 7.0 dyn/cm2) (P < 0.05).
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Role of nitric oxide in the mediation of flow-induced dilation.
The effects of 104 M
L-NAME (in the presence of
indomethacin) on flow-induced responses in arterioles of four groups of
rats are summarized in Fig. 3. This
concentration of the L-arginine analog significantly reduced flow-induced arteriolar dilation in all
groups, but to a different degree. At 25 µl/min flow, the dilation of
arterioles of males and OV females was nearly completely eliminated by
104 M
L-NAME (Fig. 3,
A and
C). In females and OVE females,
however, there was only ~50% reduction in dilation (Fig. 3,
B and
D) after L-NAME administration. In an
attempt to elucidate the mediation of the remaining flow-induced
arteriolar dilation in female and OVE female rats, Hb
(105 M), known to interfere
with the action of nitric oxide, was used. Figure 3 shows that
additional administration of Hb (in the presence of indomethacin and
104 M
L-NAME) did not further affect
the flow-diameter curve of vessels of males and OV females, whereas it
eliminated the remaining flow-induced dilation in arterioles of both
females and OVE females. Based on the flow-diameter curves depicted in
Fig. 3, values of the corresponding wall shear stress were calculated
and plotted against the changes in arteriolar diameter in Fig.
4. Administration of L-NAME displaced the shear
stress-diameter curve of vessels of female and OVE rats to the right.
The additional administration of Hb, because it prevented the dilation
in response to increases in flow, eliminated the regulation of shear
stress in these vessels. In contrast, in vessels of male and OV rats,
the administration of
104 M
L-NAME alone proved to be
sufficient to disrupt this regulation, and thus shear stress increased
linearly with increases in flow. To ascertain further that in vessels
of females the nonprostaglandin-mediated portion of the flow induced
response is entirely nitric oxide dependent, a study was performed
using a higher concentration of
L-NAME
(103 M). Figure
5 shows the results of these experiments,
demonstrating that
103 M
L-NAME eliminated flow-dependent
dilation of arterioles of female rats.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The novel finding of this study is that because of the greater release of nitric oxide, flow-induced dilation of skeletal muscle arterioles of female rats is greater than that of male rats. This gender difference, due, in large part, to the presence of estrogen, may have important consequences for the regulation of arteriolar wall shear stress and peripheral resistance in males and females.
Previous studies demonstrated that estrogen replacement therapy increases blood flow to various tissues and that this response may be due to an enhanced synthesis of nitric oxide in vascular endothelium (3, 6, 15). In vivo, the primary stimulus for the release of nitric oxide is the presence of shear stress caused by the flowing blood (9, 13). In the present study, the possible role of estrogen in affecting flow-dependent dilation was studied in four groups of rats in which the serum estrogen concentrations were significantly different. Male and OV female rats had low levels of estrogen, whereas normal female and OVE female rats had significantly higher levels of estrogen (Table 1). Ovariectomy elicited a significant reduction of plasma estrogen levels and uterus weight and a marked increase in body weight, as described previously (6).
To avoid the interference of several mechanisms that participate in the regulation of arteriolar diameter, changes in diameter to increases in perfusate flow were investigated in isolated arterioles in the presence of a constant intravascular pressure. In agreement with previous findings (6), the pressure-induced endothelium-independent myogenic tone of arterioles of female rats was significantly less pronounced than that of male rats, due to the greater synthesis/release of nitric oxide (Table 2).
Role of estrogen in augmented flow-induced dilation. In response to increases in perfusate flow, arterioles of female rats exhibited a greater dilation than arterioles of male rats. Also, the arterioles of OV females without estrogen-replacement responded in a fashion similar to those of males, but arterioles of OVE rats showed a significantly greater dilation to flow than those of males and OV females (Fig. 1). These findings suggest that the presence of higher levels of estrogen in the plasma may account for the greater flow-induced arteriolar response in female rats.
Because the stimulus for vasodilation in response to increases in flow is the increase in wall shear stress (8, 9), we calculated wall shear stress and plotted it against changes in diameter (Fig. 2). We found that shear stress-induced increases in diameter were greater, whereas the threshold for dilation tended to be lower in arterioles from rats having high plasma estrogen concentrations compared with rats with low plasma estrogen. Because of these differences, the upward portion of wall shear stress-diameter curve, indicating the level of maintained wall shear stress, was at ~20 dyn/cm2 in female arterioles and ~35 dyn/cm2 in male vessels. The lower level of maintained shear stress values recorded in vessels of males vs. those of OV rats (~45 dyn/cm2) could well be a result of a greater dilator reserve of arterioles of males due to their significantly greater passive diameter (Table 2). Extrapolating the above findings to in vivo conditions, one can speculate that resistance vessels of females (with normal plasma estrogen levels) are exposed to a lower shear stress than those of males, resulting in a lower power dissipation in the female cardiovascular system compared with that of males. If so, this could be one of the underlying mechanisms for the lower blood pressure before menopause and, perhaps, for the delayed appearance of hypertension in women compared with men.Role of nitric oxide-mediated augmentation of flow-dependent
dilation.
Although in gracilis muscle arterioles both nitric oxide and
prostaglandins contribute to the mediation of flow-induced dilation, in
a proportion of ~55 and ~45%, respectively (9), previous studies
in these arterioles suggested that it is the nitric oxide mediation
that is affected by estrogen (6). Thus, to assess solely the role of
nitric oxide in flow-dependent responses of arterioles of female rats,
vessels were pretreated with indomethacin to block prostaglandin
synthesis. In this condition, inhibition by
104 M
L-NAME eliminated flow-induced
dilation of arterioles of male and OV female rats, indicating a
complete block of nitric oxide synthase. In contrast, arterioles of
female and OVE female rats still dilated to flow in the presence of
104 M
L-NAME (Fig. 3). We hypothesized
that the remaining portion of flow-induced responses in females is due
to the incomplete block of nitric oxide synthase. To confirm our
hypothesis, we have used Hb, known to scavenge nitric oxide by forming
nitrosyl-Hb in the extracellular space. Because nitric oxide readily
crosses cell membranes, Hb provides an additional means for reducing
the level of nitric oxide before it reaches arteriolar smooth muscle. In arterioles of female and OVE rats, additional administration of Hb
(105 M) eliminated
flow-induced responses, indicating that the dilation, still present
after 104 M
L-NAME and indomethacin, is also
due to nitric oxide.
-nitro-L-arginine
(104 M) had a significantly
lesser inhibitory effect on the dilation to substance P if estrogen was
present in the plasma of rats (6).
To gain further support for the primary role for nitric oxide in female
rats, in a separate experiment a higher concentration of
L-NAME
(103 M) was used, which
completely eliminated the non-prostaglandin-mediated portion of the
dilation, suggesting that the greater flow-induced dilation is due to a
greater release of nitric oxide. This reasoning is supported further by
reports of an upregulation of nitric oxide synthase by estrogen in
vascular tissues (4, 17). A greater availability of
L-arginine, the
substrate of nitric oxide synthase, may also play a role in the greater
nitric oxide-mediated flow-induced dilation in the presence of
estrogen.
An age-dependent decline in the dilation of the brachial artery during
reactive hyperemia was reported to be delayed by a decade in women
relative to men (1). This response is also thought to be activated, at
least in part, by the increase in shear stress upon release of a
vascular occlusion, suggesting that estrogen may protect endothelial
function in women by preserving and/or enhancing the release of
nitric oxide to shear stress. Such beneficial effects of estrogen are
further underscored by the report demonstrating that estrogen
supplementation augments endothelium-dependent flow-mediated
vasodilation in the brachial artery in postmenopausal women (10).
In conclusion, the present study indicates that increases in flow/shear
stress elicit greater dilations in skeletal muscle arterioles of female
than of male rats, a difference which is due to an estrogen-stimulated
enhanced capacity of endothelial cells of arterioles from females to
produce nitric oxide in response to increases in shear stress. These
findings suggest that the presence of estrogen may play an important
role in the regulation of wall shear stress and peripheral vascular
resistance by enhancing endothelial nitric oxide release and that this
may constitute the basis for the beneficial effects of estrogen on the
cardiovascular system.
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ACKNOWLEDGEMENTS |
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We thank Miriam Nunez and Mary Browne for excellent secretarial assistance.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants P01-HL-43023 and HL-46813 and by American Heart Association, New York State Affiliate, Grants 950117 and 970137.
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 reprint requests to G. Kaley.
Received 11 March 1998; accepted in final form 6 July 1998.
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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; in presence of indomethacin), in
presence of additional 10
), and in
presence of both L-NAME and
10
) in
suffusate. * Significant difference from control or
L-NAME-treated groups.
