Vol. 283, Issue 3, H845-H852, September 2002
Effect of gender on endothelium-dependent dilation to
bradykinin in human adipose microvessels
Atsushi
Sato1,
Hiroto
Miura1,
Yanping
Liu1,
Lewis
B.
Somberg1,
Mary F.
Otterson1,
Michael J.
Demeure1,
William J.
Schulte1,
Luann M.
Eberhardt1,
Fausto R.
Loberiza1,
Ichiro
Sakuma2, and
David D.
Gutterman1
1 Departments of Internal Medicine and Surgery,
Cardiovascular Research Center, and Veterans Administration Medical
Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; and
2 Department of Cardiovascular Medicine, Hokkaido
University School of Medicine, Sapporo 060-8638, Japan
 |
ABSTRACT |
We examined the influence of gender
and climacteric status, two coronary risk factors, on bradykinin
(BK)-induced dilation in adipose arterioles from men and women of
different ages [premenopausal women (Pre-W), postmenopausal women
(Post-W), and similar aged men (Y-M and O-M), respectively]. We
examined the responses from both omental (more closely associated with
coronary disease) and subcutaneous fat. Tissues were obtained at
surgery and cannulated (60 mmHg) for measurement of internal diameter.
In vessels from omental tissue, dilation to BK was more sensitive in
Pre-W than other groups, whereas in vessels from subcutaneous tissue,
sensitivity to BK was greater in both Pre-W and Post-W compared with
Y-M and O-M. Maximal dilation was similar among groups. Indomethacin
(Indo; 10
5 M) alone had no effect on dilation to BK in
any groups, but Indo and
N
-nitro-L-arginine methyl ester
(L-NAME; 104 M) reduced dilation to BK in
Pre-W more than in Y-M. L-NAME increased dilation to BK in
subcutaneous fat from Y-M but had no effect in Post-W and O-M. Indo-
and L-NAME-resistant dilation in all vessels was markedly
reduced by 30 mM KCl. There was no difference in sodium
nitroprusside-induced dilation among groups. We conclude that gender
and climacteric state contribute to mechanisms of microvascular
regulation in humans. Functional vascular differences in visceral and
subcutaneous fat may underlie the proposed differential influence of
these tissues on cardiovascular risk.
gender; bradykinin; human vessel; endothelium
| |
INTRODUCTION |
EPIDEMIOLOGICAL
STUDIES show that cardiovascular disease is less prevalent in
premenopausal women (Pre-W) than that in age-matched men and that
cardiovascular events occur more often in postmenopausal women (Post-W)
(6, 11, 29). One proposed mechanism by which gender and
climacteric status affect cardiovascular risk is through differences in
endothelial function. In this regard, numerous studies have shown
gender differences in endothelium-dependent vasodilation not only in
animals (8, 12, 31) but also in humans (20).
Oophorectomized animals also show diminished
endothelium-dependent vasodilation (5, 19, 30). This
endothelial dysfunction may contribute to the gender and climacteric
differences in cardiac event rates.
A major mechanism by which estrogen modulates endothelial
function is through the release of nitric oxide (NO) (5, 7, 8) and altered expression of endothelial NO synthase (NOS) protein (9, 19). Non-NO-mediated dilation is also affected by estrogen (5, 15, 26). Thus it is possible that estrogen status is responsible for the difference in endothelial function between genders and climacteric state. Previous studies to assess these
questions have been performed in animals or in vivo and therefore may
have been confounded by neurohumoral and metabolic influences. To
determine the effect of gender and climacteric status directly on
vascular reactivity in humans and to examine the mechanism of dilation,
we used an isolated cannulated microvessel preparation.
The location of adipose tissue may relate to cardiovascular risk.
It is known that excess storage of lipid in visceral compared with
subcutaneous adipose is more strongly associated with cardiovascular risk factors such as the metabolic changes of hyperlipidemia and glucose intolerance (32). Because microvessels regulate
perfusion to these tissues, we hypothesized that 1) the
mechanism of arteriolar dilation to bradykinin (BK) is different in fat
from the two different sites and 2) gender and climacteric
state influence this dilation.
| |
METHODS |
Tissue acquisition and general protocol.
Otherwise discarded human omental or subcutaneous fat was obtained at
the time of abdominal surgery and placed in cold 4°C HEPES buffer
solution. Tissues were grouped according to gender and climacteric
status into one of four categories: Pre-W, Post-W, and men aged <50 yr
old (Y-M) and 
50 yr of age (O-M). Arterioles were cleaned of fat and
connective tissue and were prepared for continuous measurements of
diameter as described previously (17). Briefly, in a 20-ml
tissue chamber, both ends of the arteriole were secured to
impedance-matched glass pipettes using 10-0 Ethilon monofilament
nylon sutures (Ethicon). Vessels were bathed continuously with a cold
bicarbonate buffer [physiological saline solution (PSS)] consisting
of (in mM) 123 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 20 NaHCO3, 1.2 KH2PO4, and 11 glucose. The preparation was
then transferred to the stage of an inverted microscope (magnification ×200). Attached to the microscope were a videocamera, video monitor, and a calibrated video measurement device. Internal diameter
(resolution of 2 µm) was measured manually. Vessels were incubated in
oxygenated PSS (21% O2-5% CO2-74%
N2) for 30 min at 20 mmHg of pressure and 37°C. Pressure
was slowly increased to 60 mmHg by simultaneously adjusting the heights
of each reservoir attached to the pipettes, followed by a 30-min
incubation period.
Materials.
Endothelin-1 (ET-1) was obtained from Peninsula Laboratories. Other
chemicals were obtained from Sigma. ET-1 was prepared in saline with
1% bovine serum albumin. Indomethacin (Indo) was prepared in 0.2 M
Na2CO3. Other agents were prepared in distilled water. All concentrations represent the final steady-state
concentrations in the bath.
Experimental protocols.
All pharmacological agents were added to the external bathing
solution. After a 30-min equilibration period at 60 mmHg, vessels were
constricted with 50 mM KCl. Vessels that did not constrict >30% were
excluded (27 vessels) from analysis. Inhibitors or vehicle were added
to the chamber upon warming, recording any change in diameter.
Vascular responses to increasing concentrations of BK
(1011-106 M) were examined in the
presence and absence of
N-nitro-L-arginine methyl ester
(L-NAME; 104 M, a NOS inhibitor) and/or Indo
[105 M, a cyclooxygenase (COX) inhibitor]. Inhibitors
were added to the bath 30 min before constriction with ET-1
(1010-109 M), which was used to
constrict vessels to a goal of 30-50% of their passive diameters.
The volume of inhibitors was <1% of the circulating external bath solution.
In separate studies, we examined the effect of high K+ (30 mM)-PSS on the dilation to BK. High K+-PSS was prepared by
substitution of KCl for NaCl on an equimolar basis. Because high
K+-PSS reduced baseline diameter, in these protocols less
supplemental ET-1 was added to achieve the same degree to
preconstriction (30-50%). The endothelium-independent dilator
papaverine (104 M) was used to determine the maximal
diameter at 60 mmHg.
In a separate study, the vascular response to increasing concentrations
of sodium nitroprusside (SNP; 1010-104
M, an endothelium-independent vasodilator) was examined.
Statistical analysis.
All data are expressed as means ± SE. Percent dilation was
calculated as the percent change from the constricted diameter to the
maximal passive diameter (maximal diameter in the experiment at 60 mmHg
of luminal pressure) and was generally the diameter after papaverine
(104 M). Percent constriction was determined by
calculating the percent reduction in maximal diameter after the
application of ET-1. Statistical comparisons of maximal percent
vasodilation and ED50 (equal to 
log M) values under
different treatments were performed by paired or unpaired Student's
t-test. A two-factor repeated-measures ANOVA was used to
compare dose-response relationships between treatment groups and
comparison of Pre-W, Post-W, Y-M, and O-M. Corollary dose-specific
contrasts were treated with a Bonferroni post hoc test whenever the
interactions were statistically significant. Multiple stepwise
regression analyses were used to detect the influence of underlying
diseases, age, and gender on vasodilations at various dosages. All
procedures were done using "proc reg" programs of SAS for Windows
version 8.2. Statistical significance was defined as a value of
P < 0.05.
| |
RESULTS |
A total of 41 vessels from omental and 33 from subcutaneous fat
with mean internal diameters of 155 ± 7 and 144 ± 3 µm
(passive diameter under 60 mmHg of pressure, P = not
significant), respectively, were used.
Effect of gender on BK-induced dilation in vessels from
omental fat.
Figure 1 shows BK-induced
vasodilation in microvessels of omental fat from Pre-W and Y-M. BK
caused vasodilation in a dose-dependent manner. ED50 values
for Pre-W were greater than those for men of similar age, Y-M, whereas
maximum dilations were similar between groups (Table
1 and Fig. 1A). Thus
BK-induced dilation was greater in Pre-W than in Y-M.
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Fig. 1.
Bradykinin (BK)-induced vasodilation in the absence of
inhibitors (A), with indomethacin (Indo) alone
(B), and with Indo + N-nitro-L-arginine methyl ester
(L-NAME; C) in arterioles from omental fat.
Arterioles were contracted with endothelin (ET)-1. A:
concentration-response curve to BK
(1011-106 M) was shifted leftward in
premenopausal women (Pre-W) compared with men aged <50 yr of age
(Y-M). ED50 was greater in Pre-W vs. Y-M. Maximum dilation
was similar among groups. B: treatment with Indo did not
affect concentration-response curves to BK in either group.
C: treatment with Indo + L-NAME reduced
BK-induced dilation in Pre-W to levels similar to those observed in
Y-M. #P < 0.05 vs. Y-M. All values for
ED50 and maximum dilation are presented in Table1.
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Table 1.
Comparison of ED50 and maximum dilation to BK among the
four groups and the effect of Indo or Indo plus L-NAME on
vasodilation to BK in arterioles from omental fat tissue
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To examine the mechanism of this difference, we tested the effect of
Indo alone, Indo + L-NAME, and high
K+-PSS. Treatment with Indo alone did not affect dilation
in either gender (Fig. 1B). However, the combination of Indo
and L-NAME reduced the maximal dilation and
ED50 values in both sexes, but more in Pre-W, thereby
eliminating the gender difference (Fig. 1C). These data
suggest that NO but not prostacyclin contributes to the gender
difference in the response to BK in vessels from human omentum.
The Indo and L-NAME-insensitive component of the dilation
accounted for ~90% of the total dilator response. This component was
markedly reduced by high K+-PSS in all groups (Table
2).
Effect of gender on BK-induced dilation in vessels from
subcutaneous fat.
Figure 2 shows BK-induced vasodilation in
microvessels from subcutaneous fat in Pre-W and Y-M. ED50
values for Pre-W were greater than those for Y-M, whereas maximum
dilations were similar between groups (Table
3). Thus, similar to omentum, BK was a more potent dilator of microvessels from subcutaneous tissue in Pre-W
compared with Y-M.
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Fig. 2.
BK-induced vasodilation in the absence of inhibitors
(A), with Indo alone (B), and with Indo + L-NAME (C) in arterioles from subcutaneous fat.
Arterioles were contracted with ET-1. A:
concentration-response curve to BK
(1011-106 M) was shifted leftward in
Pre-W compared with Y-M. ED50 was greater in Pre-W than in
Y-M, although maximal dilation was similar among groups. B:
Indo did not alter the BK-induced concentration-response curves in
either group. C: treatment with Indo + L-NAME augmented BK-induced dilation in Y-M but not in
Pre-W, eliminating the difference between groups. #P < 0.05 vs. Y-M. All values for ED50 and maximum dilation are
presented in Table 3.
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Table 3.
Comparison of ED50 and maximum dilation to BK in
subcutaneous fat tissue among the four groups treated with Indo or
Indo + L-NAME
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Treatment with Indo did not affect dilation to BK in subcutaneous fat
(Table 3 and Fig. 2B); however, in contrast to omental fat,
treatment with Indo + L-NAME significantly
augmented dilation to BK in subcutaneous vessels from Y-M (Table 3),
thereby eliminating the gender difference (Fig. 2C). As with
omental vessels, the Indo- and L-NAME-insensitive dilation
of Pre-W and Y-M was markedly reduced by 30 mM KCl (Fig.
3, A and B, and
Table 2).
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Fig. 3.
Effect of high K+ (30 mM)-physiological saline solution
(PSS) on BK-induced dilation of microvessels from subcutaneous fat of
Y-M (A), Pre-W (B), and postmenopausal
women (Post-W; C). High K+-PSS markedly
inhibited the dilation that remained after treatment with Indo + L-NAME, reducing the maximal response in all groups
(P < 0.05). #P < 0.05 vs. treatment
with Indo + L-NAME. All values for ED50
and maximum dilation are presented in Table 2.
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Effect of climacteric status on BK-induced dilation in vessels from
omental and subcutaneous fat.
The effect of menopause on BK-induced dilation in vessel from omental
fat is shown in Fig. 4 and Table 1.
Vessels from Pre-W were more sensitive than those from Post-W to BK,
although maximal dilations were similar. In contrast to Pre-W, Indo or
Indo + L-NAME did not affect the dilation to BK in
Post-W (Fig. 4B).
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Fig. 4.
BK-induced dilation in the absence of inhibitors, after
Indo alone, and after treatment with Indo + L-NAME in
arterioles from omental fat tissue of Pre-W (A) and Post-W
(B). Data from Pre-W (Fig. 1) are reanalyzed for comparison.
A: in vessels from Pre-W, BK-induced dilation was not
altered by Indo alone but was significantly reduced by Indo + L-NAME. B: in contrast to Pre-W, neither Indo
alone nor Indo + L-NAME affected BK-induced dilation
in Post-W. #P < 0.05 vs. no treatment. All values for
ED50 and maximum dilation are presented in Table 1.
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There was no difference in BK-induced vasodilation between Pre-W and
Post-W in microvessels from subcutaneous fat (Fig.
5 and Table 3). K+-PSS, but
neither Indo nor Indo + L-NAME, affected dilation in either
group. The inhibitor-resistant dilation in Post-W was also markedly
reduced by 30 mM K+-PSS (Fig. 3C and Table 2).
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Fig. 5.
BK-induced dilation in the absence of inhibitors, after
Indo alone, and after treatment with Indo + L-NAME in
arterioles from subcutaneous fat tissue of Pre-W (A) and
Post-W (B). Data from Pre-W (Fig. 2) are reanalyzed for
comparison. Neither Indo alone nor Indo + L-NAME
affected BK-induced dilation both in Pre-W (A) and Post-W
(B). All values for ED50 and maximum dilation
are presented in Table 3.
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Comparison of endothelium-independent dilation and effect of
disease on BK-induced vasodilation.
Dilation to SNP was similar among the four gender-based groups in both
omental and subcutaneous fat tissues (Table
4).
Patients demographics and diagnoses are summarized in Table
5. None of the Post-W subjects were on
estrogen replacement therapy (ERT). We evaluated the influence of age,
gender, climacteric status, and underlying diseases (diabetes,
hypertension, hypercholesterolemia, congestive heart failure, coronary
artery disease, or myocardial infarction) on vasodilation to BK and SNP
in vessels from omental and subcutaneous fat. With the use of
multivariable regression analysis, it was determined that BK-induced
vasodilation in subcutaneous fat was reduced in men (P < 0.05) but not altered by disease. In omental fat tissue, only
menopause reduced dilation to BK (P < 0.05). No factor
affected SNP-induced dilation.
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DISCUSSION |
The key findings of this study are fourfold. First, microvessels
from omental tissue in Pre-W are more sensitive to BK than Post-W or
men. Second, in vessels from subcutaneous fat, BK-induced vasodilation
is greater in women than in men. Third, inhibition of NOS eliminates
these gender and climacteric differences. Finally, endothelium-independent responses are similar between genders in both
types of tissue. Taken together, these data indicate that BK-induced
dilation in peripheral microvessels from human fat tissue is
predictably affected by both gender and hormonal state. Furthermore,
these findings are novel in demonstrating a different mechanism of
microvascular reactivity in similarly sized vessels from adipose tissue
in different parts of the body.
Contribution of gender and climacteric status to BK-induced
vasodilation in omental fat tissue.
In the present study, we demonstrated that sensitivity to BK-induced
vasodilation in microvessels from omentum was greater in Pre-W than in
Y-M. This is the first report of gender differences in human adipose
arteriolar vasoreactivity. Our data are consistent with animal studies
(8, 12, 31) and with human studies of brachial conduit
(20) and resistance (4) arterial dilation in
vivo. Our data also indicate a prominent effect of menopause on human
peripheral microvascular reactivity. In addition, we observed an
important role for NOS in this gender and climacteric difference. In
omental tissue, inhibiting NOS eliminated the enhanced sensitivity to
BK in Pre-W compared with men, in agreement with previous studies in
the rat employing acetylcholine as the endothelium-dependent agonist
(31).
Contribution of gender and climacteric status to vasodilation in
subcutaneous fat.
Similar to omental vessels, BK-induced dilation in subcutaneous fat was
greater in Pre-W than in Y-M. However, in contrast to omental tissue,
there was no significant contribution of NO to the dilation in
subcutaneous vessels from women. Unexpectedly, Indo + L-NAME but not Indo alone increased dilation to BK in
subcutaneous arterioles from Y-M at lower doses, eliminating the gender
difference. Several potential mechanisms could explain this unexpected finding.
First, because NOS can produce superoxide under conditions of reduced
cofactors or substrate (22), and because
L-NAME can inhibit NOS-induced superoxide production
(10, 13), we speculate that L-NAME may have
inhibited the production of superoxide in Y-M, thereby reducing the
inhibitory effect of superoxide on subcutaneous arteriolar dilation to
BK. This is consistent with previous reports that superoxide levels are
higher in the vasculature of normal male than female rats
(3). The combination of generated superoxide and NO may
lead to formation of peroxynitrite, a more destructive reactive species
that can impair dilation (25). Second, because NO can
potently inhibit cytochrome P-450 epoxygenase
(2) and because this enzyme is responsible for generating
a common form of endothelium-dependent hyperpolarizing factor
(EDHF), epoxyeicostrieonic acid, we speculate that
L-NAME-mediated enhancement of dilation could be due to the
release of inhibition of EDHF by NO levels that are subthreshold for
dilation. Third, the differential gender response may also relate to a
different endothelial cell calcium sensitivity (24).
Clinical implications.
Subcutaneous and visceral adipose tissues, although similar in
their role of energy storage and fat accumulation, differ in terms of
their association with cardiovascular risk. Visceral fat accumulation
is more closely linked to insulin resistance and to the progression of
atherosclerosis than subcutaneous fat (32). Obesity with
excessive visceral fat is a significant risk for cardiovascular disease
that is also influenced by gender. Pre-W (14) and Post-W
with ERT (28) show lower visceral fat accumulation than
age-matched men and Post-W without ERT. This gender difference may
relate to different rates of lipolysis because norepinephrine-induced
lipolysis is greater in men than in women (16). NO
released from adipocytes may contribute to the lower rate of lipolysis
(1). We speculate that if NO derived from vascular
endothelium also inhibits lipolysis in visceral fat, it may prevent
elevation of serum free fatty acids that are linked to insulin
resistance in Pre-W. Understanding of the role of the endothelial
modulation of blood flow in fat may lead to new insights on vascular
responses in insulin resistance syndromes.
Study limitations.
We classified women according to menopausal status but did not
measure plasma estrogen levels. Therefore, we could not correlate findings with estrogen levels. Furthermore, because the exact timing of
the onset of menopause was not available, we cannot rule out the
possibility that some women classified as postmenopausal were actually
perimenopausal or only recently postclimacteric. If this were the case,
the differences we observed would only underestimate the quantitative
and not affect the qualitative changes associated with menopause.
None of the enrolled women were taking hormone replacement
therapy. Obtaining tissue from patients on replacement therapy may
further address the role of estrogens on adipose vascular reactivity.
As demonstrated in Table 5, patients in the older groups (Post-W
and O-M) were more likely to have ischemic heart disease or
cardiovascular risk factors. It is also likely that they were taking
more medications. Because we did not record medication regimens, this
may limit the comparison between subjects based on age.
The accumulation of excess visceral fat is considered a risk
factor for coronary artery disease (CAD). We did not quantify visceral
fat, nor did we obtain patient weight or body mass index as an
indication of obesity. However, we speculate that the different mechanism of dilation in visceral compared with subcutaneous fat arterioles may relate to the significance of visceral fat as a risk
factor for CAD. In future studies, the relationship between obesity and
visceral fat content and BK-induced dilation should be determined. It
may be that vascular abnormalities in obese subjects impair visceral
but not subcutaneous mechanisms of vasodilation.
Experiments using the COX inhibitor Indo alone indicate that
prostacyclin or other vasodilator prostanoids do not contribute to
BK-induced dilation of adipose arterioles. However, only a few studies
were performed using the NOS inhibitor L-NAME alone; thus
conclusions about the role of NO must be tempered by the fact that Indo
was present in most of these experiments. Demonstrated interactions
between NO and COX (27) could influence these results. However, two factors favor the involvement of an NO mechanism when
Indo + L-NAME together were effective. First, because
Indo alone did not alter dilation to BK, products of COX metabolism are
likely not involved. Second, in a limited number of studies (n = 8 vessels, data not shown) where
L-NAME alone was used, the associated reduced (omental) or
enhanced (subcutaneous) dilation to BK was similar to that seen with
the combination of inhibitors.
Previous studies demonstrate that the response to BK is dependent
on the vascular bed studied, with activation of different receptor
populations producing qualitatively different responses. In the porcine
basilar artery, BK induces either contraction or relaxation through
endothelial B2 receptor-mediated PGH2 or NO formation, respectively(18). On the other hand, in the
porcine iliac artery, low doses of BK show NO-mediated relaxation via B2 receptors and high doses yield contraction, by combined
activation of B1 and B2 receptors
(21). The differential effect of BK in omental and
subcutaneous tissue could derive in part from a different pattern of BK
receptor activation.
In conclusion, the mechanism of dilation to BK in human adipose
tissue depends on gender, climacteric status, and tissue location. Endothelium-derived NO contributes to gender and climacteric
differences in BK-induced microvascular dilation from omental fat in
premenopausal subjects. In microvessels from subcutaneous fat, NO also
contributes to gender differences, but by a different mechanism
involving reduced BK-mediated dilation in male subjects.
| |
ACKNOWLEDGEMENTS |
This work was supported by American Heart Association, Northland
Affiliate, Postdoctoral Fellowship Grant 0020565Z, National Heart,
Lung, and Blood Institute Grant HL-65203, the Veterans Administration,
and the Gutterman Foundation.
| |
FOOTNOTES |
Address for reprint requests and other correspondence:
D. D. Gutterman, Dept. of Internal Medicine, Cardiovascular
Center, and Veterans Administration Medical Center, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail: dgutt{at}mcw.edu).
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.
May 9, 2002;10.1152/ajpheart.00160.2002
Received 4 March 2002; accepted in final form 4 May 2002.
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