(Circulation. 1996;93:577-584.)
© 1996 American Heart Association, Inc.
Articles |
Estrogen Reduces Myointimal Proliferation After Balloon Injury of Rat Carotid Artery
From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, University of Alabama at Birmingham.
Correspondence to Suzanne Oparil, MD, University of Alabama at Birmingham, 1034 Zeigler Research Bldg, Birmingham, AL 35294-0007.
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Abstract |
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Background Vascular disease progresses more slowly in females with functional ovaries than in males. The mechanisms of this vasoprotective effect of female sex are incompletely understood. This study tested (1) whether there is a sex difference in the development of myointimal proliferation after balloon injury of the rat carotid artery in vivo, (2) whether this response is estrogen or androgen dependent, and (3) whether there is a sexual dimorphism in expression of the c-myc proto-oncogene in intact and/or damaged rat carotid arteries.
Methods and Results Ten-week-old male and female Sprague-Dawley rats were either gonadectomized or studied intact. Gonadectomized rats of both sexes were implanted with estradiol, testosterone, or nothing (control) 3 days before vascular injury. Two weeks later, the rats were killed by overdose of pentobarbital, and the injured right and uninjured control left carotid arteries were fixed and subjected to morphometric analysis for evaluation of the degree of myointimal thickening. Separate groups of intact male and female rats were killed at 1 and 2 hours after vascular injury, and total RNA from injured and uninjured vessels was subjected to Northern blot analysis for assessment of steady state c-myc mRNA levels. Neointimal area and the ratio of neointimal to medial area were significantly less in intact female rats than in intact male rats (P<.05). Gonadectomy of female rats was associated with a greater increase in neointima formation after balloon injury than that observed in intact females (P<.05), but testosterone replacement did not further enhance this response. Estradiol treatment significantly inhibited myointimal proliferation after vascular injury in gonadectomized rats of both sexes (P<.05). Neither gonadectomy nor gonadectomy plus testosterone replacement altered the myointimal proliferative response to balloon injury in male rats. Steady state c-myc mRNA levels were detectable in undamaged carotid arteries in intact rats of both sexes and were significantly greater in males than in females; c-myc mRNA levels were increased in both sexes after carotid injury, but the response was significantly larger in magnitude and more rapid in males than in females.
Conclusions These data indicate that the sex difference in myointimal proliferation after vascular injury is estrogen dependent. C-myc gene expression is greater in the undamaged carotid artery of the male than in that of the female, and the responsiveness of this gene to balloon injury of the artery is more rapid and more robust in the male than in the female rat. These findings have direct implications for the prevention and treatment of vascular disease in humans.
Key Words: stenosis • hormones • genes
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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A sexually dimorphic pattern in the development of atherosclerotic vascular diseases in humans has been observed in epidemiological and clinical studies.1 The incidence of cardiovascular disease is lower in premenopausal women than in age-matched men but rises steadily after menopause.2 Postmenopausal women given estrogen replacement therapy appear to have less severe coronary artery disease and a lower risk for cardiovascular mortality than women without hormone treatment.3 Thus, estrogens exert an inhibitory effect on the development of cardiovascular disease in women.4 The mechanism of this vasoprotective effect is incompletely understood. Approximately 30% to 50% of the antiatherosclerotic effects of estrogens in humans have been attributed to alterations in plasma lipid and lipoprotein levels, principally elevations in HDL cholesterol, HDL2, and apolipoprotein A-1.2 5 However, since retardation in arterial lesion development can occur in response to estrogen (17ß-estradiol) treatment in the absence of alterations in serum cholesterol levels, other effects must account for some of the vasoprotection afforded by these compounds.6 Estrogens have direct vasoprotective effects, including enhancement of endothelial degradation of LDL cholesterol, antioxidant actions on LDL particles in macrophages, suppression of collagen and elastin synthesis, and restoration of endothelium-dependent vasodilator mechanisms postinjury.7 8 9 10 11 12 Furthermore, administration of estrogen to male normotensive rats decreases the pressor response to norepinephrine, arginine vasopressin, and KCl by inhibiting Ca2+ influx through voltage-dependent Ca2+ channels.13 Estrogen also stimulates prostacyclin biosynthetic activity in cultured rat aortic smooth muscle cells.14 Thus, estrogens affect vascular wall structure and function via a number of distinct mechanisms.
Balloon injury of the arteries of animals (including rabbit, fowl, swine, and primates) has been widely used as an experimental model for the early injury phase of atherosclerosis.15 In this model, inflation of the balloon denudes endothelium and induces a highly reproducible intimal migration/proliferation of smooth muscle cells over the entire length of the affected vessel. The objectives of the current study were to develop a suitable rat model to examine the sex-related development of vascular disease and to test (1) whether there is a sexual dimorphism in the development of myointimal proliferation after balloon injury; (2) if so, whether this dimorphism is estrogen or androgen dependent; and (3) whether there is a sex difference in expression of the c-myc proto-oncogene after balloon injury of the carotid artery in intact rats. We previously demonstrated increased expression of c-myc in balloon-injured rat carotid arteries and demonstrated that mithramycin (a G-C–specific binding drug that selectively inhibits transcription of genes such as c-myc that have G-C–rich promoter sequences) prevents myointimal proliferation in this model.16 In the current study, we hypothesized that estrogen might prevent myointimal proliferation in response to balloon injury of the carotid artery, at least in part, by inhibiting expression of c-myc.
Our results demonstrated that (1) myointimal proliferation after balloon injury of the carotid artery is reduced in intact female Sprague-Dawley rats compared with age-matched males, providing a model for further study of the mechanisms of sex differences in the pathogenesis of vascular disease; (2) the sexual dimorphism of myointimal proliferation after balloon injury of the rat carotid artery is dependent on estrogen; (3) exogenous estrogen can prevent neointima formation in damaged vessels of gonadectomized rats of both sexes; and (4) c-myc gene expression in the undamaged carotid artery is less in intact female rats than in intact males and is less responsive to balloon injury of the vessel in the female than in the male rat. These findings have direct implications for the prevention and treatment of vascular disease in humans.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Animals
Ten-week-old male and female Sprague-Dawley rats were obtained from Charles River Breeding Laboratories (Wilmington, Mass). All rats were maintained at constant humidity (60±5%), temperature (24±1°C), and light cycle (6 AM to 6 PM) and were fed a standard rat pellet diet (Ralston Purina Diet) ad libitum. All protocols were approved by the Institutional Animal Care and Use Committee at the University of Alabama at Birmingham and were consistent with the Guide for the Care and Use of Laboratory Animals (NIH publication 85-23, revised 1985). Body weights were determined before and 2 weeks after balloon injury of the carotid artery.
Gonadectomy and Hormone-Replacement
Therapy
Male and female Sprague-Dawley rats were randomly
divided into four subgroups. The first group remained intact (n=11
male; n=7 female). The second group was subjected to castration or
ovariectomy and implanted subcutaneously with empty silicone elastomer
capsules made from Dow Corning Silastic medical grade tubing (1.57 mm
IDx3.18 mm OD, Dow Corning Corp) (n=6 male; n=6 female).
The third
group was subjected to castration or ovariectomy and was implanted
subcutaneously with 10-mm silicone elastomer capsules packed with
17ß-estradiol (Sigma Chem Co) (n=6 male; n=5 female), and
the
fourth group was subjected to castration or ovariectomy and implanted
subcutaneously with 15-mm silicone elastomer capsules packed with
crystalline testosterone propionate (Sigma Chem Co) (n=7 male;
n=5
female). Gonadectomy and implantation of the silicone
elastomer capsules were performed under light ether
anesthesia 3 days and 6 days after arrival in the
laboratory, respectively. The capsules were sealed with silicone
elastomer adhesive type A (Dow Corning Corp). All capsules were
preincubated in PBS (0.01 mol/L PO4, 0.15 mol/L
NaCl, pH 7.4) at 37°C for 24 hours before insertion. The 10-mm and
15-mm capsules filled with 17ß-estradiol and testosterone
propionate were shown in previous studies to raise serum estradiol and
testosterone levels to the ranges normally found in intact adult female
and male rats.17 18
Balloon-Injury Procedure
Rats were anesthetized with sodium
pentobarbital (50
mg/kg IP), and the right carotid artery was isolated by a middle
cervical incision, suspended on ties, and stripped of adventitia. The
distal right common carotid artery and region of the bifurcation were
exposed. A 2F Fogarty balloon catheter (Baxter V. Mueller) was
introduced through the external carotid artery and advanced into the
thoracic aorta. The balloon was inflated with saline to distend the
common carotid artery and was pulled back to the external carotid
artery. After six repetitions of this procedure, the
endothelium was removed completely, and there was some
injury to medial smooth muscle layers throughout the common carotid
artery. After removal of the catheter, the external carotid artery was
ligated and the wound closed. The left carotid artery was not damaged
and served as a control.
Morphometric Analysis
Two weeks after balloon injury of the
right carotid artery, rats
were killed with an overdose of sodium pentobarbital (75 mg/kg) and
perfused with 10% formalin at a pressure of 120 mm Hg. The vascular
system was rinsed with 10 mL of PBS before infusion of fixative
solution. Both carotid arteries were isolated from adherent tissue and
fixed in 10% formalin for morphometric analysis. Vessels were
embedded in paraffin, and the middle fifth (0.2 cm) of the damaged
right carotid artery was serially sectioned (30 µm). The left carotid
artery was not damaged and served as a control. Morphometric
analysis of each arterial segment was performed
with a computer-based Bioquant II Morphometric system. Tissue was
stained with Verhoeff's elastic tissue stain, which demonstrated
several layers of elastic laminae (Fig 1
). At least five
sections of each vessel were examined, and the measurements were
averaged for statistical analysis. All morphometric
analyses were carried out by a single examiner, who was blinded
with respect to the experimental group to which each sample belonged.
The cross-sectional surface areas of the vessel within the external
elastic lamina (total area), within the internal elastic lamina
(intimal area), and within the lumen (lumen area) were measured. The
degree of myointimal proliferation of the injured carotid artery was
expressed as the absolute area of neointima and the ratio
of the neointimal area to the medial area.
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Gonadal Hormone Assays
At the time the rats were killed,
adequacy of hormone
replacement was determined by taking a 1 mL blood sample from the
femoral arterial cannula. Serum testosterone levels in
intact males and in castrated males receiving testosterone replacement
and serum estradiol levels in intact females and in ovariectomized
females receiving 17ß-estradiol replacement were determined by
radioimmunoassay with commercially available kits
(Diagnostic Products Corporation). Assay sensitivity
was 0.4 ng/mL and 8 pg/mL for testosterone and estradiol, respectively.
Intra-assay and interassay coefficients of variation were
respectively 6.0% and 7.9% for testosterone and 5.3% and 6.4% for
estradiol.
RNA Isolation and Northern Blot Analysis
In a separate
experiment, rats were killed by an overdose of
sodium pentobarbital (75 mg/kg IP) at 1 and 2 hours after vascular
injury. Fresh tissue was collected, rapidly frozen in liquid nitrogen,
and stored at -70°C. Total RNA was extracted from undamaged
left carotid arteries and balloon-injured right carotid arteries by
the method of Chomczynski and Sacchi.19 Thirty micrograms
of total RNA (pooled from six arteries) was denatured at 65°C for 5
minutes in 50% formamide and 6% formaldehyde (in 22.5 mmol/L MOPS
with 1.2 mmol/L EDTA), size fractionated by electrophoresis through
1.5% agarose/3% formaldehyde gels (in 20 mmol/L MOPS, 5 mmol/L sodium
acetate, 1 mmol/L EDTA, pH 7.0), and blotted onto Nytran membrane (0.45
µm, Schleicher & Schuell Inc) in 20x SSC. Northern blots were
ultraviolet cross-linked (Bio-Rad), prehybridized in QuickHyb
hybridization buffer (Stratagene) for 15 minutes, and hybridized in the
same buffer with a 32P-labeled mouse c-myc cDNA
probe20 at 68°C for 1 hour. After hybridization, blots
were washed twice in 500 mL 2x SSC, 0.1% SDS at room temperature for
15 minutes and twice in 0.1x SSC, 0.1% SDS at 60°C for 20 minutes.
Blots were partially dried and exposed to x-ray film (Kodak X-OMAT
film, Sigma Chem Co). To quantitate total RNA loaded on each lane,
blots were stripped by washing in 5 mmol/L Tris-HCl (pH 8.0), 0.2
mmol/L Na2 EDTA, 0.05% sodium pyrophosphate, 0.002% PVP,
0.002% BSA, and 0.002% sucrose at 70°C for 3 hours and rehybridized
with a commercially available cDNA probe of the housekeeping gene GAPDH
(Ambion) under the conditions specified above. The GAPDH mRNA levels
were used as internal controls to normalize the densitometric data to
account for variations in RNA loading. The density of
autoradiographic signals was quantitated with an
optical densitometer (model GS-670 Imaging Densitometer, Bio-Rad). To
estimate vessel steady state c-myc mRNA levels, the ratio of
c-myc mRNA to GAPDH mRNA was determined by dividing the
absorbance corresponding to mouse c-myc cDNA probe
hybridization by the absorbance corresponding to GAPDH mRNA probe
hybridization.
Statistical Analysis
Results were expressed as
mean±SE. Data were analyzed
by use of the CRUNCH statistical package on an IBM PC/AT
computer. Statistical comparisons of body weight,
neointimal area, medial area, total area, lumen area, ratio
of neointimal area to medial area, and ratio of
c-myc mRNA to GAPDH mRNA among experimental groups were
performed by use of two-way ANOVA. A value of P<.05 was
considered significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Two weeks after balloon injury of the right carotid artery, body weights of both intact and gonadectomized female Sprague-Dawley rats were significantly less than those of comparable groups of males (Table
). Castrated male rats
weighed significantly less than their intact counterparts, and
testosterone replacement restored the body weights of castrated male
rats to the same range as intact males. In contrast, estradiol
treatment was associated with a significant reduction in body weight of
castrated male rats, into the same range as gonadectomized females.
Gonadectomy in the female, unlike the male, was
associated with a significant increase in body weight. Testosterone
replacement did not alter the body weight of gonadectomized females,
but estradiol replacement lowered it into the same range as intact
females. Serum testosterone levels in intact males and in castrated
males receiving testosterone replacement were 2.0±0.8 ng/mL
(n=4) and
7.5±1.0 ng/mL (n=6), respectively. Serum estradiol levels in
intact
females and in ovariectomized females receiving 17ß-estradiol
replacement were 51.9±5.8 pg/mL (n=4) and 135.0±5.7 pg/mL
(n=5),
respectively. The normal range of serum testosterone levels in intact
male rats reported in the literature is 3.5 to 22 ng/mL.18
The normal range of serum estradiol levels in intact female rats
reported in the literature is 30 to 500 pg/mL, depending on the stage
of the estrus cycle.17 Our intact female rats were not
staged at the time of balloon injury or at the time they were killed;
the gonadectomized rats clearly did not cycle.
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In the undamaged left carotid artery, the intima was a single
cell-layer thick; the internal elastic lamina was intact and the
external elastic lamina was in contact with the adventitia in all rats
examined. There were no differences in the total area or the medial
area (wall thickness) of the undamaged left carotid artery among
experimental groups, indicating that the anatomy of the intact
carotid artery was not significantly different between the sexes and
was not significantly altered by either gonadectomy or
gonadectomy plus hormone replacement (Table
and Fig
1).
The only exception was the small but significant reduction in total
area in gonadectomized, estradiol-replaced female rats compared
with intact females (Table).
Two weeks after balloon injury of the right carotid artery, myointimal
proliferation was reduced in intact female Sprague-Dawley
rats compared with intact males (Figs 2 and 3).
Significant proliferation of the
neointima, consisting of circumferentially uniform,
multiple layers of smooth muscle cells, was observed in the damaged
vessel in intact male and gonadectomized male and female rats that did
not receive estradiol (Figs 2 and 3).
Furthermore, the internal elastic
lamina was disrupted. Extensive neointimal proliferation
was associated with reduced residual lumen areas in these groups
(Table). In estradiol-treated rats of both sexes, the degree of
neointimal proliferation of the damaged carotid artery was
less extensive than in the respective intact male and female groups
(Figs 2 and 3).
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Morphometric analysis showed that the neointimal
area and the ratio of neointimal area to medial area were
significantly less in intact female rats than in age-matched intact
males (Figs 2 through 4). Neither
gonadectomy nor gonadectomy plus
testosterone replacement of male rats altered the myointimal
proliferative response to balloon injury (Figs 2 and
4).
Gonadectomy of female rats was associated with a
markedly increased myointimal proliferative response to injury, but
testosterone replacement did not enhance this response further (Figs
3 and 4). Administration of estradiol
significantly suppressed myointima
formation in gonadectomized rats of both sexes compared with
intact and gonadectomized male and female rats without estradiol
treatment (Figs 2 through 4).
Lumen sizes were significantly decreased
in intact males and gonadectomized rats of both sexes without estradiol
treatment (Figs 2 and 4; Table).
There was no significant change in the
total area or the medial area of damaged carotid arteries compared with
undamaged vessels in any experimental group (Table and Figs
2 and 3).
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Northern blot analysis showed that steady state
c-myc mRNA levels were significantly greater in uninjured
carotid arteries of intact male rats than in intact females (Fig
5). Vascular injury was associated with significant
increases in c-myc mRNA levels in male rats at 1 and 2 hours
after the insult (+648% and +667%, respectively, compared with
uninjured left carotid artery controls). In female rats,
c-myc mRNA levels were unchanged at 1 hour and significantly
increased at 2 hours (+430% compared with uninjured left carotid
artery controls). Thus, the c-myc response to balloon injury
was both more prompt and more robust in the male than in the female
rat.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Our results demonstrated that (1) myointimal proliferation after balloon injury of the carotid artery was significantly greater in intact male Sprague-Dawley rats than in age-matched intact females; (2) neither gonadectomy nor gonadectomy plus testosterone replacement in male rats altered the myointimal proliferative response to balloon injury; (3) gonadectomy of female rats was associated with a more robust myointimal proliferative response to injury, comparable to that seen in male rats, but testosterone replacement did not further enhance this response; and (4) estradiol replacement markedly attenuated neointima formation in gonadectomized rats of both sexes. Thus, the sexual dimorphism of myointimal proliferation after balloon injury of the rat carotid artery is estrogen dependent.
The most dramatic finding of the current study was that administration
of 17ß-estradiol to gonadectomized rats of both sexes inhibited
the myointimal response to vascular injury by 
60%, an effect
greater than that previously observed in our laboratory with
mithramycin16 and comparable to results observed with a
variety of other agents in the rat carotid injury model.21
These results are consistent with previous observations that
estrogen replacement therapy significantly inhibits coronary
artery atherosclerosis in ovariectomized monkeys and in
cholesterol-fed chicks22 23 and that
estradiol attenuates myointimal hyperplasia in rabbit cardiac and
aortic allografts and after balloon injury in
vivo.24 25 26
Estradiol has been shown to inhibit hyperlipemic serum-induced
thymidine uptake by explants of pig coronary artery and rabbit
aortic medial tissue in vitro.27 28 Foegh et
al26 found that treatment with estradiol for 72 hours
after balloon injury of rabbit aorta inhibited thymidine incorporation
and reduced the DNA content of injured vessels. Together, these studies
suggest that the effect of estrogen on the myointimal proliferative
response to vascular injury, whether related to
hyperlipidemia, transplantation, or mechanical trauma,
may be due to inhibition of smooth muscle cell proliferation through
autocrine and paracrine mechanisms.
It is likely that estrogen modulates vascular smooth muscle cell proliferation by activating a specific estrogen receptor that is expressed by the smooth muscle cells. Specific binding of estrogen to vascular cells has been described in a number of animal studies.29 30 Autoradiography has demonstrated that [3H]-estradiol-17ß is distributed in the cytosol and nuclei of cells in all three layers of the vessel wall.27 Orimo et al31 detected estrogen receptor mRNA by Northern blot analysis in vascular smooth muscle cells derived from rat aorta. Lin et al32 reported that administration of estradiol-17ß affects the intracellular distribution of estrogen receptors and elevates progesterone receptor content in ovariectomized female baboons, suggesting that estrogen receptors are physiologically functional in primate vascular cells. Furthermore, Karas and coworkers33 reported that human vascular smooth muscle cells express estrogen receptor mRNA and protein and that this receptor is capable of estrogen-dependent gene activation, suggesting a mechanism by which estrogen may directly alter vascular smooth muscle cell function. Recently, Losordo et al34 showed evidence of estrogen receptors in coronary artery specimens of female patients by use of immunohistochemical staining and in human vascular smooth muscle cells by use of radioligand binding and gel retardation assays. In that study,34 a majority of normal arteries and a minority of atherosclerotic vessels were positive for estrogen receptor expression. The inverse relation between estrogen receptor expression and presence of coronary atherosclerosis was highly significant in premenopausal subjects only. These findings suggest that estrogen receptor expression by target cells in the arterial wall, as well as circulating estrogen levels, may play a functional role in vasoprotection.
In the current study, steady state mRNA levels for c-myc were significantly greater in uninjured carotid arteries of intact male rats than in intact females. C-myc is an immediate early-response gene that is expressed in nearly all cell types and appears to play an important role in regulating cellular proliferation and differentiation.35 Levels of c-myc mRNA and protein are highest before DNA synthesis (S phase) and remain increased throughout the cell cycle in the presence of growth factors. The increase in c-myc transcript levels in arteries of male rats compared with females suggests that blood vessels are growing more rapidly and that smooth muscle cells, the predominant cell type in the carotid artery, are dividing more rapidly in the male than in the female. Further study is needed to determine whether this sexual dimorphism in vascular growth is estrogen dependent.
C-myc gene expression can be induced by various mitogens,36 by serum stimulation of smooth muscle cells in culture,37 and by balloon injury of rat and rabbit aorta in vivo.16 38 39 The mitogenic effect of estrogen on estrogen-responsive human breast cancer cells has been related to c-myc expression.40 Estrogen receptor–positive cell lines manifest a more than tenfold induction in c-myc expression within 1 to 2 hours of estradiol exposure, whereas in estrogen receptor–negative cell lines, expression of c-myc is unaffected by either estradiol or the estrogen antagonist tamoxifen citrate. C-myc antisense oligomers reduce c-myc expression and inhibit proliferation of vascular smooth muscle cells in culture,37 and mithramycin (a G-C–specific DNA binding drug that selectively inhibits transcription of genes such as c-myc that have G-C–rich promoter sequences) inhibits transcription of c-myc and prevents myointimal proliferation after balloon injury of the rat carotid artery in vivo.16 The magnitude of the increment in c-myc expression observed in male rats at 1 and 2 hours after vascular injury in the current study was comparable to that observed in male Sprague-Dawley rats in our previous study.16 In contrast, c-myc expression was not increased in females at 1 hour after injury, and both the absolute level and the magnitude of increase at 2 hours postinjury were far less in female than in male rats. Thus, there appears to be a sexual dimorphism in the expression of this early-response gene in the setting of acute vascular injury, with the female being less responsive than the male. This suggests that estrogen reduces the expression of c-myc in vascular smooth muscle cells in response to injury. This is directly opposite to the effects of estrogen on breast cancer cells. The dichotomy in these regulatory mechanisms merits further investigation.
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Acknowledgments |
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This work was supported in part by grants HL-44195, HL-47081, HL-48848, HL-07457, and HL-50147 from the National Heart, Lung, and Blood Institute and a Grant-in-Aid (No. 93014269) from the American Heart Association. The authors thank Nancy Penney for her assistance in the preparation of this manuscript.
Received July 27, 1995; revision received September 19, 1995; accepted September 25, 1995.
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