(Circulation. 1996;94:2221-2227.)
© 1996 American Heart Association, Inc.
Articles |
Medroxyprogesterone Attenuates Estrogen-Mediated Inhibition of Neointima Formation After Balloon Injury of the Rat Carotid Artery
the University of Alabama at Birmingham, Vascular Biology and Hypertension Program.
Correspondence to Suzanne Oparil, MD, 1034 Zeigler Research Bldg, 703 S 19th St, Birmingham, AL 35294-0007.
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Background Estrogen blunts the neointimal proliferative response to balloon injury of the carotid artery in intact female rats and gonadectomized rats of both sexes. This study tested whether, in gonadectomized rats of both sexes, (1) progestin (medroxyprogesterone acetate, MPA) alters neointima formation in injured carotid arteries, (2) addition of MPA alters the antiproliferative effects of estrogen, and (3) an interaction between MPA and estrogen can be accounted for by MPA-induced alterations in serum 17ß-estradiol levels.
Methods and Results Male and female Sprague-Dawley rats were subjected to gonadectomy, then were randomly divided into four subgroups and treated with either (1) 17ß-estradiol, (2) MPA, (3) 17ß-estradiol+MPA, or (4) vehicle, and balloon injury of the right common carotid artery was carried out. Two weeks later, rats were killed by overdose of pentobarbital, and the carotid arteries were subjected to morphometric analysis for evaluation of myointimal thickening. Estradiol inhibited myointimal proliferation after vascular injury in gonadectomized rats of both sexes (P<.05). MPA alone did not alter neointima formation, but addition of MPA to estradiol completely blocked the antiproliferative effects of estrogen without altering serum 17ß-estradiol levels.
Conclusions These data indicate that exogenous progestin given alone does not alter the vascular injury response in the rat carotid injury model but that addition of a progestin blocks the antiproliferative effects of estrogen in this model. These effects are seen in gonadectomized rats of both sexes. These findings have direct implications for postmenopausal hormone replacement therapy in humans.
Key Words: restenosis • hormones • women • carotid arteries • vasculature
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It is generally believed that atherosclerosis is initiated by injury to the vessel wall.1 Vascular injury can be due to a variety of factors, including hyperlipidemia, oxidative stress, hypertension, and vessel disruption caused by bypass surgery or balloon catheter inflation. Vascular smooth muscle cell (VSMC) proliferation is an integral part of the response to vascular injury. VSMCs, which normally have a contractile phenotype, migrate into the subendothelial region of the vessel, proliferate, change to a secretory phenotype, and synthesize and secrete extracellular matrix proteins after vascular injury.
Estrogen inhibits atherosclerosis, as first demonstrated by Stamler et al2 in cholesterol-fed chickens more than 40 years ago. Subsequent studies have suggested that this effect is mediated, in large part, by estrogen-induced inhibition of the migration, growth, and proliferation of VSMCs. Animal models of vascular injury have been used to examine the effects of estrogen on VSMC proliferation in vivo.3 4 5 6 7 In these models, vascular injury induces a highly reproducible intimal migration/proliferation of VSMCs over the entire length of the affected vessel, mimicking the early injury phase of atherosclerosis. Studies have shown that estrogen inhibits the VSMC response to vascular injury in these models. 17ß-Estradiol has been shown to inhibit neointimal formation (VSMC proliferation and extracellular matrix formation) after balloon injury of the common and external iliac arteries of rabbits.3 Experiments carried out in the mouse carotid injury model of Lindner et al8 have shown that gonadectomy enhances and physiological levels of 17ß-estradiol replacement suppress subintimal hyperproliferation in vessels damaged by repetitive passage of angioplasty wires in female mice.4 Studies carried out in our own laboratory in the rat carotid injury model have shown that intact female rats have a reduced myoproliferative response to vascular injury compared with intact males and that exogenous estrogen prevents neointima formation in damaged vessels of gonadectomized rats of both sexes.5 Thus, both endogenous and exogenous estrogen inhibit the vascular injury response.
Studies in both humans and experimental animals have suggested that addition of a progestin, although it is needed to prevent the hyperplastic/neoplastic effects of unopposed estrogen on the endometrium, may reduce the beneficial effects of estrogen replacement therapy on the risk of cardiovascular disease.9 10 11 Accordingly, it is critical to understand the effects of progestins, alone and in combination with estrogen, on the vascular response to injury. The present study examined this question by use of the rat carotid injury model. Specifically, the study tested whether exogenous progestin (medroxyprogesterone acetate, MPA) alters neointima formation in balloon-injured carotid arteries of gonadectomized male and female Sprague-Dawley rats, whether addition of MPA alters the antiproliferative effects of exogenous estrogen in the damaged carotid artery of gonadectomized rats, and whether an interaction between MPA and estrogen can be accounted for by MPA-induced alterations in serum 17ß-estradiol levels. Our results demonstrated that (1) exogenous progestin did not alter neointima formation in balloon-injured carotid arteries of gonadectomized Sprague-Dawley rats of both sexes and (2) addition of MPA completely blocked the antiproliferative effects of exogenous estrogen on the damaged carotid artery of gonadectomized rats without altering serum 17ß-estradiol levels. These findings have direct implications for postmenopausal hormone replacement therapy in humans.
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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 published by the National Institutes of Health (NIH publication No. 85-23, revised 1985). Body weights were determined before and 2 weeks after balloon injury of the carotid artery.
Gonadectomy and Hormone Therapy
Three days after arrival in the laboratory, all rats were subjected to castration or ovariectomy under light ether anesthesia. Three days after gonadectomy, male and female rats were randomly divided into four subgroups, and hormone therapy was initiated. The first treatment group (n=8 male; n=6 female) received daily injections of estrogen (17ß-estradiol 20 µg/kg in 100 µL cottonseed oil SC daily); the second (n=8 male; n=7 female) received progestin (MPA, 10 mg/kg in 100 µL saline SC daily); the third (n=6 male; n=7 female) received estrogen+progestin in the doses described above given daily as separate injections; and the fourth (n=10 male; n=11 female) received vehicle (100 µL cottonseed oil SC daily). The 17ß-estradiol and MPA were purchased from Sigma Chemical Co.
Balloon Injury Procedure
After 3 days of hormone therapy, 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 then 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 one 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. 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 unaware of 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 (luminal 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, a 1-mL blood sample was removed from the femoral arterial cannula and allowed to clot. Serum estradiol and progesterone levels were determined by radioimmunoassay with commercially available kits (Diagnostic Products Corp). Assay sensitivity was 8 pg/mL for estradiol and 30 pg/mL for progesterone. Intra-assay and interassay coefficients of variation were 5.3% and 6.4% for estradiol and 4.7% and 7.9% for progesterone. The estradiol antiserum is highly specific for 17ß-estradiol, with low cross-reactivity with 17
-estradiol (0.017%), estriol (0.32%), aldosterone (0%), progesterone (0%), cortisol (0%), testosterone (0.001%), and 5-dihydrosterone (0.004%). The progesterone antiserum is highly specific for progesterone, with no cross-reactivity (0%) with MPA, estradiol, cortisol, testosterone, or pregnenolone.
Statistical Analysis
Results were expressed as mean±SEM. Data were analyzed with the CRUNCH statistical package on an IBM 486 computer. Statistical comparisons of body weight, neointimal area, medial area, total area, luminal area, and ratio of neointimal area to medial area among experimental groups were performed with two-way ANOVA. Differences were reported as significant at a value of P<.05.
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Two weeks after balloon injury of the right carotid artery, body weights of all groups of female SD rats were significantly less than those of comparable groups of males (Table
). Estradiol treatment was associated with a decrease in body weight in both male and female groups compared with controls. MPA treatment did not alter body weight compared with control groups. Treatment with the combination of MPA and estradiol resulted in decreased body weight in both sexes.
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Serum estradiol and progesterone levels are summarized in the Table
and Fig 1. Serum 17ß-estradiol levels were increased twofold to threefold in estrogen-treated rats of both sexes compared with vehicle-treated gonadectomized rats. 17ß-Estradiol levels in estrogen-treated male (21.8±3.2 pg/mL) and female (34.1±6.2 pg/mL) rats were within or close to the normal range of serum estradiol levels for intact female rats reported in the literature (30 to 50 pg/mL, depending on the stage of the estrous cycle12 ) and were comparable to the values for intact 12- to 14-week-old female Sprague-Dawley rats obtained in our laboratory (36.6±3.8 pg/mL). Serum estradiol levels were significantly greater in estrogen-treated gonadectomized female rats than in gonadectomized males, despite equivalent doses of administered estrogen (adjusted for body weight). MPA treatment alone did not alter serum estradiol levels in gonadectomized male rats from values obtained during vehicle treatment, but it lowered estradiol levels significantly in ovariectomized female rats compared with vehicle-treated controls. Addition of MPA to estradiol treatment did not alter serum estradiol levels in females but elevated estradiol levels in castrated males to values significantly greater than those in similarly treated ovariectomized females. Serum estradiol levels did not differ significantly between estrogen-treated and estrogen+MPA–treated ovariectomized female rats; they were significantly higher in castrated male rats receiving both treatments than in those receiving estrogen alone.
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Serum progesterone levels (Table and Fig 1, bottom) were not significantly different in vehicle-treated male and female rats and were increased in males but not in females in response to estrogen treatment. MPA treatment, alone and in combination with estrogen, caused progesterone levels to fall to barely measurable levels. This is probably due to suppression of native progesterone by the artificial progestin, which does not cross-react with antibodies raised to native progesterone.
Both the damaged right and undamaged left carotid arteries were examined histologically after perfusion fixation at 2 weeks after injury. 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 hormone treatment.
Two weeks after balloon injury of the right carotid artery, myointimal proliferation was less in estradiol-treated rats of both sexes than in vehicle-treated gonadectomized rats (Table and Figs 2 through 5). Significant proliferation of the neointima, consisting of circumferentially uniform, multiple layers of smooth muscle cells, was observed in the damaged vessel in vehicle-treated gonadectomized male and female rats (Figs 2 and 3). Furthermore, the internal elastic lamina was disrupted. In estradiol-treated rats of both sexes, the degree of neointimal proliferation in the damaged carotid artery was less extensive than in the respective vehicle-treated gonadectomized male and female groups (Table and Figs 2 and 3). MPA treatment alone did not alter the myointimal proliferative response to balloon injury in gonadectomized rats of either sex (Table and Figs 2 and 3). The degree of neointimal proliferation in the damaged carotid artery of MPA-treated rats was not significantly different from that in vehicle-treated rats and was significantly greater than in estradiol-treated rats. In rats treated with MPA+estradiol, the degree of neointimal proliferation in the damaged carotid artery was not significantly different from that in gonadectomized rats treated with vehicle or MPA alone and was significantly greater than in estradiol-treated rats (Table and 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 rats of both sexes treated with estradiol alone than in any other treatment group (Table and Figs 4 and 5). The intimal area was reduced by 43% in estrogen-treated males and by 67% in estrogen-treated females. Neither MPA alone nor MPA+estradiol treatment of either male or female rats altered the myointimal proliferative response to balloon injury compared with vehicle-treated groups (Table and Figs 4 and 5). Administration of estradiol significantly suppressed neointima formation in gonadectomized rats of both sexes compared with other treatments; addition of MPA to estradiol blocked this effect and restored the myoproliferative response to levels seen in rats treated with vehicle or MPA alone (Table and Figs 4 and 5).
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Our results demonstrated that (1) estradiol treatment in doses that produced physiological levels of circulating hormone markedly attenuated neointima formation after balloon injury of the carotid artery in gonadectomized rats of both sexes, (2) MPA treatment did not alter the myointimal proliferative response to balloon injury, and (3) addition of MPA to estradiol treatment abolished the estrogen-mediated inhibition of neointima formation in gonadectomized rats of both sexes without altering circulating estradiol levels. Thus, MPA completely blocked the vasoprotective effect of estrogen in this model.
The most dramatic finding of the present study was that administration of MPA to gonadectomized rats of both sexes completely blocked the estradiol-mediated inhibition of the myointimal response to vascular injury. These results are consistent with previous observations that addition of progestins to estrogen therapy reduces the beneficial effects of estrogen on cardiovascular risk and the atherosclerotic process. Progestin-mediated reductions in the beneficial effects of estrogen replacement therapy on cardiovascular risk have been attributed to effects on lipid metabolism and thrombosis (hemostasis) in humans, and adverse effects on endothelial function, lipid metabolism, and atherosclerotic lesion formation have been demonstrated in animal models.
Lipid/lipoprotein effects have been hypothesized to account for 
50% of the cardioprotective action of postmenopausal hormone replacement therapy with orally administered conjugated estrogen. In contrast, transdermal estradiol, a delivery system similar to the subcutaneous administration used in the present study, has little or no effect on lipid levels but can inhibit LDL oxidation.13 The enhanced efficacy of oral compared with parenteral estrogen may relate to the high concentrations of estrogens delivered to the hepatocytes by the portal circulation after intestinal absorption.
Orally administered estrogens raise HDL cholesterol levels in humans by at least two mechanisms: suppressing hepatic lipase activity, thus reducing conversion of HDL2 to HDL3, and increasing synthesis of apolipoprotein.14 Estrogens lower LDL cholesterol by accelerating LDL catabolism, probably by increasing the density of LDL receptors.15 16 Postmenopausal estrogen treatment has also been shown to reduce levels of lipoprotein(a), a lipoprotein with structural features of LDL and plasminogen, which is believed to be atherogenic and thrombogenic.17
In addition to altering lipid/lipoprotein synthesis and degradation, estrogen reduces the atherogenicity of LDL by inhibiting its oxidation in vitro and in vivo.13 18 It is well established that oxidative modification of LDL greatly increases its atherogenicity and that antioxidants may reduce the extent of atherosclerosis in animals and cardiovascular events in humans.19 Accordingly, estrogen may be contributing to the prevention of cardiovascular events in women via its antioxidant effect.
Progestins have been hypothesized to blunt the beneficial effects of estrogens on lipoproteins,20 21 22 and clinical trials have shown that women taking unopposed oral estrogen have significantly greater increases in HDL cholesterol than those taking oral estrogen plus a synthetic progestin.23 24 25 26 The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial showed that both unopposed estrogen and estrogen plus micronized progesterone regimens were more effective in raising HDL cholesterol levels than were regimens that included estrogen plus either cyclic or continuous MPA.9 However, all hormone replacement regimens produced significant increases in HDL cholesterol and decreases in LDL cholesterol levels compared with placebo. Thus, estrogen alone or in combination with a progestin improves the lipid profile in postmenopausal women, but the magnitude of the improvement is less if MPA is included in the regimen.
Progesterone treatment of ovariectomized/hysterectomized baboons fed a high-cholesterol/high-saturated-fat diet has been shown to increase LDL and VLDL cholesterol levels and accelerate atherosclerotic plaque development.27 HDL cholesterol was unaffected. Estrogen treatment reduced LDL cholesterol levels and the (VLDL+LDL)/HDL cholesterol ratio and decreased plaque formation, whereas the combination of estrogen+progesterone had a smaller effect on lipids but reduced plaque formation to a greater extent than estrogen alone. The authors interpreted these results as evidence that progesterone increases atherosclerosis in this model and that the concomitant administration of estrogen completely reverses the atherogenic effect of progesterone.
Antagonism of the antithrombotic effects of estrogen by progestin has been reported in postmenopausal women.28 Postmenopausal women on estrogen replacement therapy and premenopausal women have lower levels of plasminogen activator inhibitor-1 and higher levels of tissue plasminogen activator in serum than postmenopausal women not treated with estrogen, whereas women taking estrogen+progestin have higher levels of plasminogen activator inhibitor-1 than women on unopposed estrogen. This suggests another mechanism by which progestin may oppose the vasoprotective effects of estrogen, ie, by opposing its fibrinolytic effects.
Studies in ovariectomized animal models have shown that hormone replacement therapy has vasoprotective effects that are not accompanied by changes in plasma lipid levels. Estrogen treatment retarded arterial lesion development in rabbits without affecting serum cholesterol levels.29 Treatment of female cynomolgus monkeys with an intravaginal ring containing the synthetic progestin levonorgestrel was associated with greater atherosclerotic plaque formation than treatment with oral contraceptives containing both estrogen and progesterone, despite similar reductions in plasma HDL cholesterol in both groups.30 Furthermore, hormone replacement therapy with 17ß-estradiol+cyclic progesterone has been shown to reduce the accumulation of LDL cholesterol in coronary arteries of ovariectomized cynomolgus monkeys without altering circulating lipid levels.31 Thus, the sex hormones modulate the atherosclerotic process via mechanisms that are independent of alterations in lipoprotein levels and appear to involve the vessel wall directly. The present study focused on the direct effects of estrogen and progestin on the response to vascular injury in a rodent model, in which lipids are not considered to play a role.
Whether progestins antagonize the vasoprotective effects of estrogen in animal models of vascular injury and atherosclerosis is controversial. Estrogen and progestin have been shown to have opposing effects on vascular remodeling in the aorta of the hypertensive rat.32 Estrogen treatment of male rats with experimentally induced renovascular hypertension reduced aortic wall thickness, medial area, and collagen and elastin content to normotensive control levels without lowering blood pressure. In contrast, progestin treatment tended to increase aortic thickness, medial area, and total protein content. Thus, estrogen and progestin had important and opposing modulatory effects on the response to vascular injury in a rodent model with low endogenous lipid levels.
In contrast, addition of cyclic progesterone treatment has been shown not to attenuate the antiatherosclerotic effect of continuously administered estrogen in ovariectomized cynomolgus monkeys.33 After 30 months of eating a high-fat diet, monkeys treated with continuous 17ß-estradiol alone or continuous 17ß-estradiol+intermittent crystalline progesterone showed a 50% reduction in coronary artery atherosclerosis compared with untreated controls. Plasma lipid levels were unaffected. In addition, coadministration of a synthetic (contraceptive) progestin with an estrogen did not accelerate atherogenesis in a monkey model despite decreasing plasma HDL levels.34 35 More recently, the effects of MPA and of combination treatment with MPA+conjugated equine estrogen in the ovariectomized cynomolgus monkey model were compared with conjugated equine estrogen alone and with vehicle treatment.36 After 30 months of treatment, the monkeys treated with estrogen alone showed a 70% decrease in extent of atherosclerosis compared with untreated controls and with animals treated with MPA alone or MPA+estrogen. The two MPA-treated groups were not significantly different from untreated controls. Combined MPA+estrogen treatment or MPA treatment alone resulted in 170% and 290% increases, respectively, in extent of atherosclerosis compared with estrogen treatment alone. Furthermore, coadministration of MPA with estrogen tended to increase plasma LDL and decrease plasma HDL levels. These findings suggest that MPA antagonizes the atheroprotective effects of unopposed estrogen, consistent with the results of the present study.
The apparent inconsistency among studies of the effects of progestin-estrogen interactions on atherosclerosis and the vascular injury response undoubtedly relates, in part, to differences in progestin preparations (synthetic progestins with androgenic properties versus naturally occurring progesterone), doses of progestin and progestin:estrogen dose ratios, and the animal preparation under study. A clear understanding of this relationship, and therefore of the effects of postmenopausal hormone replacement therapy on the vasculature, awaits further study of the mechanisms by which the sex hormones modulate the growth and proliferation of VSMCs and endothelial cells (ECs). Interactions at the receptor level have been described that could account for some of the experimental findings discussed previously. In cardiovascular tissues, expression of progesterone receptors can be induced in response to estrogen acting through estrogen receptors,37 and several putative estrogen response elements have been identified in the rat progesterone receptor gene that can form a strong estrogen-responsive enhancer when linked together.38
An alternative, estrogen receptor–independent pathway by which progesterone could oppose the vasoprotective effects of estrogen has been suggested by the recent observation that progesterone stimulates the synthesis of thrombospondin-1 in human endometrial stromal cells in culture.39 Thrombospondin-1 inhibits EC adhesion, migration, and proliferation. By stimulating thrombospondin-1 production by VSMCs and/or ECs, progesterone could oppose the effects of estrogen on ECs and VSMCs (increased adhesion, migration, and proliferation of ECs and increased NO production), thus retarding reendothelialization and enhancing the neointimal response to injury.
Estrogen augments the activity and steady-state mRNA levels of the constitutive nitric oxide synthases in the vasculature,40 an effect that both enhances endothelium-dependent vasodilation and inhibits thrombosis by preventing platelet aggregation, platelet and inflammatory cell adhesion to the vessel wall, and release of factors that stimulate VSMC migration and proliferation.41 42 Progestin inhibits the estrogen-induced augmentation of NO synthesis and release by unknown mechanisms.43 Further studies are needed to determine whether these mechanisms are expressed in the injured blood vessel and whether they play a functional role in the vascular injury response.
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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 Grant-in-Aid 93014269 from the American Heart Association. The authors thank Nancy Penney and Dianne Shields for their assistance in the preparation of this manuscript.
Received April 8, 1996; revision received May 23, 1996; accepted May 27, 1996.
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