(Circulation. 1996;93:577-584.)
© 1996 American Heart Association, Inc.
Articles |
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.
| Abstract |
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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
| Introduction |
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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-Cspecific binding drug that selectively inhibits transcription of genes such as c-myc that have G-Crich 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.
| Methods |
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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.
|
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.
| Results |
|---|
|
|
|---|
|
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
).
|
|
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
).
|
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.
|
| Discussion |
|---|
|
|
|---|
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 receptorpositive cell lines manifest a more than tenfold induction in c-myc expression within 1 to 2 hours of estradiol exposure, whereas in estrogen receptornegative 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-Cspecific DNA binding drug that selectively inhibits transcription of genes such as c-myc that have G-Crich 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.
| Acknowledgments |
|---|
Received July 27, 1995; revision received September 19, 1995; accepted September 25, 1995.
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V. M. Miller and S. P. Duckles Vascular Actions of Estrogens: Functional Implications Pharmacol. Rev., June 1, 2008; 60(2): 210 - 241. [Abstract] [Full Text] [PDF] |
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V. L. Ballard and J. M. Edelberg Harnessing Hormonal Signaling for Cardioprotection Sci. Aging Knowl. Environ., December 21, 2005; 2005(51): re6 - re6. [Abstract] [Full Text] [PDF] |
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D. K. Jagadeesha, T. E. Lindley, J. DeLeon, R. V. Sharma, F. Miller, and R. C. Bhalla Tempol therapy attenuates medial smooth muscle cell apoptosis and neointima formation after balloon catheter injury in carotid artery of diabetic rats Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1047 - H1053. [Abstract] [Full Text] [PDF] |
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F. A. Yaghini, C. Zhang, J.-H. Parmentier, A. M. Estes, N. Jafari, S. A. Schaefer, and K. U. Malik Contribution of Arachidonic Acid Metabolites Derived Via Cytochrome P4504A to Angiotensin II-Induced Neointimal Growth Hypertension, June 1, 2005; 45(6): 1182 - 1187. [Abstract] [Full Text] [PDF] |
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M. Jayachandran, R. Mukherjee, T. Steinkamp, P. LaBreche, M. P. Bracamonte, H. Okano, W. G. Owen, and V. M. Miller Differential effects of 17{beta}-estradiol, conjugated equine estrogen, and raloxifene on mRNA expression, aggregation, and secretion in platelets Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2355 - H2362. [Abstract] [Full Text] [PDF] |
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K. Hashimura, K. Sudhir, J. Nigro, S. Ling, M. R. I. Williams, P. A. Komesaroff, and P. J. Little Androgens Stimulate Human Vascular Smooth Muscle Cell Proteoglycan Biosynthesis and Increase Lipoprotein Binding Endocrinology, April 1, 2005; 146(4): 2085 - 2090. [Abstract] [Full Text] [PDF] |
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A. P. Miller, W. Feng, D. Xing, N. M. Weathington, J. E. Blalock, Y.-F. Chen, and S. Oparil Estrogen Modulates Inflammatory Mediator Expression and Neutrophil Chemotaxis in Injured Arteries Circulation, September 21, 2004; 110(12): 1664 - 1669. [Abstract] [Full Text] [PDF] |
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C. Zhang, J. Yang, and L. K. Jennings Attenuation of neointima formation through the inhibition of DNA repair enzyme PARP-1 in balloon-injured rat carotid artery Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H659 - H666. [Abstract] [Full Text] [PDF] |
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C. Maric, K. Sandberg, and C. Hinojosa-Laborde Glomerulosclerosis and Tubulointerstitial Fibrosis are Attenuated with 17{beta}-Estradiol in the Aging Dahl Salt Sensitive Rat J. Am. Soc. Nephrol., June 1, 2004; 15(6): 1546 - 1556. [Abstract] [Full Text] [PDF] |
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Y. Li, I. Kishimoto, Y. Saito, M. Harada, K. Kuwahara, T. Izumi, I. Hamanaka, N. Takahashi, R. Kawakami, K. Tanimoto, et al. Androgen Contributes to Gender-Related Cardiac Hypertrophy and Fibrosis in Mice Lacking the Gene Encoding Guanylyl Cyclase-A Endocrinology, February 1, 2004; 145(2): 951 - 958. [Abstract] [Full Text] [PDF] |
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D. Xing, A. Miller, L. Novak, R. Rocha, Y.-F. Chen, and S. Oparil Estradiol and Progestins Differentially Modulate Leukocyte Infiltration After Vascular Injury Circulation, January 20, 2004; 109(2): 234 - 241. [Abstract] [Full Text] [PDF] |
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J. Kawagoe, M. Ohmichi, T. Takahashi, C. Ohshima, S. Mabuchi, K. Takahashi, H. Igarashi, A. Mori-Abe, M. Saitoh, B. Du, et al. Raloxifene Inhibits Estrogen-induced Up-regulation of Telomerase Activity in a Human Breast Cancer Cell Line J. Biol. Chem., October 31, 2003; 278(44): 43363 - 43372. [Abstract] [Full Text] [PDF] |
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A. P. Miller, Y.-F. Chen, D. Xing, W. Feng, and S. Oparil Hormone Replacement Therapy and Inflammation: Interactions in Cardiovascular Disease Hypertension, October 1, 2003; 42(4): 657 - 663. [Abstract] [Full Text] [PDF] |
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J. Mehilli, A. Kastrati, H. Bollwein, A. Dibra, H. Schuhlen, J. Dirschinger, and A. Schomig Gender and restenosis after coronary artery stenting Eur. Heart J., August 2, 2003; 24(16): 1523 - 1530. [Abstract] [Full Text] [PDF] |
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L. C. Zacharia, R. K. Dubey, Z. Mi, and E. K. Jackson Methylation of 2-Hydroxyestradiol in Isolated Organs Hypertension, July 1, 2003; 42(1): 82 - 87. [Abstract] [Full Text] [PDF] |
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M. van Eickels, R. D. Patten, M. J. Aronovitz, A. Alsheikh-Ali, K. Gostyla, F. Celestin, C. Grohe, M. E. Mendelsohn, and R. H. Karas 17-Beta-Estradiol increases cardiac remodeling and mortality in mice with myocardial infarction J. Am. Coll. Cardiol., June 4, 2003; 41(11): 2084 - 2092. [Abstract] [Full Text] [PDF] |
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P. Y. Liu, A. K. Death, and D. J. Handelsman Androgens and Cardiovascular Disease Endocr. Rev., June 1, 2003; 24(3): 313 - 340. [Abstract] [Full Text] [PDF] |
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M. Jayachandran, W. G. Owen, and V. M. Miller Effects of ovariectomy on aggregation, secretion, and metalloproteinases in porcine platelets Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1679 - H1685. [Abstract] [Full Text] [PDF] |
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F. C. W. Wu and A. von Eckardstein Androgens and Coronary Artery Disease Endocr. Rev., April 1, 2003; 24(2): 183 - 217. [Abstract] [Full Text] [PDF] |
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N. A. Nussmeier, M. R. Marino, and W. K. Vaughn Hormone replacement therapy is associated with improved survival in women undergoing coronary artery bypass grafting J. Thorac. Cardiovasc. Surg., December 1, 2002; 124(6): 1225 - 1229. [Abstract] [Full Text] |
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K. J. Ho and J. K. Liao Nonnuclear Actions of Estrogen Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 1952 - 1961. [Abstract] [Full Text] [PDF] |
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K. L. Chambliss and P. W. Shaul Estrogen Modulation of Endothelial Nitric Oxide Synthase Endocr. Rev., October 1, 2002; 23(5): 665 - 686. [Abstract] [Full Text] [PDF] |
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E. K. Jackson Commentary on Liu et al: Effect of Estrogen and AT1 Receptor Blocker on Neointima Formation Hypertension, October 1, 2002; 40(4): 448 - 450. [Full Text] [PDF] |
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K. J. Ho and J. K. Liao Non-nuclear Actions of Estrogen: New Targets for Prevention and Treatment of Cardiovascular Disease Mol. Interv., July 1, 2002; 2(4): 219 - 228. [Abstract] [Full Text] [PDF] |
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D. G. Espinosa-Heidmann, I. Suner, E. P. Hernandez, W. D. Frazier, K. G. Csaky, and S. W. Cousins Age as an Independent Risk Factor for Severity of Experimental Choroidal Neovascularization Invest. Ophthalmol. Vis. Sci., May 1, 2002; 43(5): 1567 - 1573. [Abstract] [Full Text] [PDF] |
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H. Brady, S. Desai, L. M. Gayo-Fung, S. Khammungkhune, J. A. McKie, E. O'Leary, L. Pascasio, M. K. Sutherland, D. W. Anderson, S. S. Bhagwat, et al. Effects of SP500263, a Novel, Potent Antiestrogen, on Breast Cancer Cells and in Xenograft Models Cancer Res., March 1, 2002; 62(5): 1439 - 1442. [Abstract] [Full Text] [PDF] |
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T. Tolbert, J. A. Thompson, P. Bouchard, and S. Oparil Estrogen-Induced Vasoprotection Is Independent of Inducible Nitric Oxide Synthase Expression: Evidence From the Mouse Carotid Artery Ligation Model Circulation, November 27, 2001; 104(22): 2740 - 2745. [Abstract] [Full Text] [PDF] |
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S. Ling, G. Deng, H. E. Ives, K. Chatterjee, G. M. Rubanyi, P. A. Komesaroff, and K. Sudhir Estrogen inhibits mechanical strain-induced mitogenesis in human vascular smooth muscle cells via down-regulation of Sp-1 Cardiovasc Res, April 1, 2001; 50(1): 108 - 114. [Abstract] [Full Text] [PDF] |
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R. K. Dubey and E. K. Jackson Estrogen-induced cardiorenal protection: potential cellular, biochemical, and molecular mechanisms Am J Physiol Renal Physiol, March 1, 2001; 280(3): F365 - F388. [Abstract] [Full Text] [PDF] |
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N. Sudoh, K. Toba, M. Akishita, J. Ako, M. Hashimoto, K. Iijima, S. Kim, Y.-Q. Liang, Y. Ohike, T. Watanabe, et al. Estrogen Prevents Oxidative Stress-Induced Endothelial Cell Apoptosis in Rats Circulation, February 6, 2001; 103(5): 724 - 729. [Abstract] [Full Text] [PDF] |
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B. Chandrasekar and J.-F. Tanguay Local delivery of 17-beta-estradiol decreases neointimal hyperplasia after coronary angioplasty in a porcine model J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1972 - 1978. [Abstract] [Full Text] [PDF] |
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S. Jovanovic, A. Jovanovic, W. K. Shen, and A. Terzic Low concentrations of 17{beta}-estradiol protect single cardiac cells against metabolic stress-induced Ca2+ loading J. Am. Coll. Cardiol., September 1, 2000; 36(3): 948 - 952. [Abstract] [Full Text] [PDF] |
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G. G. Geary, D. N. Krause, and S. P. Duckles Estrogen reduces mouse cerebral artery tone through endothelial NOS- and cyclooxygenase-dependent mechanisms Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H511 - H519. [Abstract] [Full Text] [PDF] |
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G. G. Geary, D. N. Krause, and S. P. Duckles Gonadal hormones affect diameter of male rat cerebral arteries through endothelium-dependent mechanisms Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H610 - H618. [Abstract] [Full Text] [PDF] |
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L. D Horwitz and E. A Rosenthal The authors' reply Vascular Medicine, May 1, 2000; 5(2): 128 - 128. [PDF] |
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Y. K. Hodges, L. Tung, X.-D. Yan, J. D. Graham, K. B. Horwitz, and L. D. Horwitz Estrogen Receptors {alpha} and {beta} : Prevalence of Estrogen Receptor {beta} mRNA in Human Vascular Smooth Muscle and Transcriptional Effects Circulation, April 18, 2000; 101(15): 1792 - 1798. [Abstract] [Full Text] [PDF] |
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R. H. Karas, J. B. Hodgin, M. Kwoun, J. H. Krege, M. Aronovitz, W. Mackey, J. A. Gustafsson, K. S. Korach, O. Smithies, and M. E. Mendelsohn Estrogen inhibits the vascular injury response in estrogen receptor beta -deficient female mice PNAS, December 21, 1999; 96(26): 15133 - 15136. [Abstract] [Full Text] [PDF] |
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S. Oparil, S.-J. Chen, Y.-F. Chen, J. N Durand, L. Allen, and J. A Thompson Estrogen attenuates the adventitial contribution to neointima formation in injured rat carotid arteries Cardiovasc Res, December 1, 1999; 44(3): 608 - 614. [Abstract] [Full Text] [PDF] |
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G. Li, Y.-F. Chen, G. L. Greene, S. Oparil, and J. A. Thompson Estrogen Inhibits Vascular Smooth Muscle Cell-Dependent Adventitial Fibroblast Migration In Vitro Circulation, October 12, 1999; 100(15): 1639 - 1645. [Abstract] [Full Text] [PDF] |
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L. Zhang, M. C. Fishman, and P. L. Huang Estrogen Mediates the Protective Effects of Pregnancy and Chorionic Gonadotropin in a Mouse Model of Vascular Injury Arterioscler Thromb Vasc Biol, September 1, 1999; 19(9): 2059 - 2065. [Abstract] [Full Text] [PDF] |
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N. Harada, H. Sasano, H. Murakami, T. Ohkuma, H. Nagura, and Y. Takagi Localized Expression of Aromatase in Human Vascular Tissues Circ. Res., June 11, 1999; 84(11): 1285 - 1291. [Abstract] [Full Text] [PDF] |
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S. Makela, H. Savolainen, E. Aavik, M. Myllarniemi, L. Strauss, E. Taskinen, J.-A. Gustafsson, and P. Hayry Differentiation between vasculoprotective and uterotrophic effects of ligands with different binding affinities to estrogen receptors alpha and beta PNAS, June 8, 1999; 96(12): 7077 - 7082. [Abstract] [Full Text] [PDF] |
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V M Miller Gender and vascular reactivity Lupus, June 1, 1999; 8(5): 409 - 415. [Abstract] [PDF] |
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Y. K. Hodges, J. K. Richer, K. B. Horwitz, and L. D. Horwitz Variant Estrogen and Progesterone Receptor Messages in Human Vascular Smooth Muscle Circulation, May 25, 1999; 99(20): 2688 - 2693. [Abstract] [Full Text] [PDF] |
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S. Doolen, D. N. Krause, and S. P. Duckles Estradiol modulates vascular response to melatonin in rat caudal artery Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1281 - H1288. [Abstract] [Full Text] [PDF] |
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M. L Kuroski de Bold Estrogen, natriuretic peptides and the renin-angiotensin system Cardiovasc Res, March 1, 1999; 41(3): 524 - 531. [Abstract] [Full Text] [PDF] |
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S. Oparil Hormones and Vasoprotection Hypertension, January 1, 1999; 33(1): 170 - 176. [Abstract] [Full Text] [PDF] |
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P. Holm, H. L. Andersen, G. Arroe, and S. Stender Gender Gap in Aortic Cholesterol Accumulation in Cholesterol-Clamped Rabbits : Role of the Endothelium and Mononuclear-Endothelial Cell Interaction Circulation, December 15, 1998; 98(24): 2731 - 2737. [Abstract] [Full Text] [PDF] |
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P. Zandberg, J. L. M. Peters, P. N. M. Demacker, M. J. Smit, E. G. de Reeder, and D. G. Meuleman Tibolone Prevents Atherosclerotic Lesion Formation in Cholesterol-Fed, Ovariectomized Rabbits Arterioscler Thromb Vasc Biol, December 1, 1998; 18(12): 1844 - 1854. [Abstract] [Full Text] [PDF] |
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V. Lindner, S. K. Kim, R. H. Karas, G. G. J. M. Kuiper, J.-A. Gustafsson, and M. E. Mendelsohn Increased Expression of Estrogen Receptor-ß mRNA in Male Blood Vessels After Vascular Injury Circ. Res., July 27, 1998; 83(2): 224 - 229. [Abstract] [Full Text] [PDF] |
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G. G. Geary, D. N. Krause, and S. P. Duckles Estrogen reduces myogenic tone through a nitric oxide-dependent mechanism in rat cerebral arteries Am J Physiol Heart Circ Physiol, July 1, 1998; 275(1): H292 - H300. [Abstract] [Full Text] [PDF] |
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D. Somjen, F. Kohen, A. Jaffe, Y. Amir-Zaltsman, E. Knoll, and N. Stern Effects of Gonadal Steroids and Their Antagonists on DNA Synthesis in Human Vascular Cells Hypertension, July 1, 1998; 32(1): 39 - 45. [Abstract] [Full Text] [PDF] |
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E. Van Belle, C. Bauters, T. Asahara, and J. M. Isner Endothelial regrowth after arterial injury: from vascular repair to therapeutics Cardiovasc Res, April 1, 1998; 38(1): 54 - 68. [Full Text] [PDF] |
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D. F. Skafar, R. Xu, J. Morales, J. Ram, and J. R. Sowers Female Sex Hormones and Cardiovascular Disease in Women J. Clin. Endocrinol. Metab., December 1, 1997; 82(12): 3913 - 3918. [Abstract] [Full Text] [PDF] |
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C. R. White, J. Shelton, S.-J. Chen, V. Darley-Usmar, L. Allen, C. Nabors, P. W. Sanders, Y.-F. Chen, and S. Oparil Estrogen Restores Endothelial Cell Function in an Experimental Model of Vascular Injury Circulation, September 2, 1997; 96(5): 1624 - 1630. [Abstract] [Full Text] |
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K. Krasinski, I. Spyridopoulos, T. Asahara, R. van der Zee, J. M. Isner, and D. W. Losordo Estradiol Accelerates Functional Endothelial Recovery After Arterial Injury Circulation, April 1, 1997; 95(7): 1768 - 1772. [Abstract] [Full Text] |
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I. Spyridopoulos, A. B. Sullivan, M. Kearney, J. M. Isner, and D. W. Losordo Estrogen-Receptor–Mediated Inhibition of Human Endothelial Cell Apoptosis : Estradiol as a Survival Factor Circulation, March 18, 1997; 95(6): 1505 - 1514. [Abstract] [Full Text] |
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S. Oparil, R. L. Levine, S.-J. Chen, J. Durand, and Y.F. Chen Sexually Dimorphic Response of the Balloon-Injured Rat Carotid Artery to Hormone Treatment Circulation, March 4, 1997; 95(5): 1301 - 1307. [Abstract] [Full Text] |
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R. L. Levine, S.-J. Chen, J. Durand, Y.-F. Chen, and S. Oparil Medroxyprogesterone Attenuates Estrogen-Mediated Inhibition of Neointima Formation After Balloon Injury of the Rat Carotid Artery Circulation, November 1, 1996; 94(9): 2221 - 2227. [Abstract] [Full Text] |
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K. Hisamoto, M. Ohmichi, H. Kurachi, J. Hayakawa, Y. Kanda, Y. Nishio, K. Adachi, K. Tasaka, E. Miyoshi, N. Fujiwara, et al. Estrogen Induces the Akt-dependent Activation of Endothelial Nitric-oxide Synthase in Vascular Endothelial Cells J. Biol. Chem., January 26, 2001; 276(5): 3459 - 3467. [Abstract] [Full Text] [PDF] |
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