disease claims the lives of 500 000 women in the
United States every year.1 Although
women are largely protected from clinical coronary disease before the
menopause, they rapidly develop increased risk thereafter.2 Both
experimental and clinical data suggest that this loss of protection results
from a deficiency of endogenous estrogens. Estrogen replacement therapy
markedly attenuates the development of dietary atherosclerosis in
ovariectomized monkeys.3 4 In epidemiological
studies, postmenopausal women taking estrogen
replacement therapy experience up to 50%
fewer adverse coronary events, with
the greatest benefit occurring in women with coronary artery disease.5 6 These
observations indicate that estrogen replacement therapy
may have an important role in primary and secondary prevention of
therapy intended to reduce the risk of fatal and nonfatal
myocardial infarction or of sudden coronary death must alter the biology of
atherosclerosis, prevent plaque rupture (the proximate cause of sudden coronary
occlusion), or reduce its consequences. Vulnerable plaques typically contain a
large pool of extracellular lipid, surrounded by a dense inflammatory
infiltrate, and are covered by only a thin fibrous cap.7 8 9 10 11 12 Estrogen,
directly or indirectly, might retard the development of such plaques, favorably
affect the vulnerability of existing plaques, or reduce the risk of coronary
occlusion by preventing formation of an occlusive thrombus, a consequence of
plaque rupture.13 14 In
addition, estrogen may attenuate vasomotor dysfunction, a possible trigger of
plaque rupture. Estrogen may protect
women from cardiovascular disease in part through modification of the lipid
profile. Premenopausal women have reduced LDL and elevated HDL cholesterol
compared with men.15 After
menopause, women develop a more atherogenic lipid profile as LDL cholesterol
levels rise, HDL cholesterol levels fall, and lipoprotein(a) levels increase.16 17 18 19 20 Estrogen
replacement reverses these adverse changes in lipoprotein profile and
diminishes cardiovascular risk.21 22 23 24 However, multiple regression analyses of large-scale
inferences drawn from the decrease in cardiovascular events in men associated
with lipid profile modification indicate that the beneficial changes in
lipoprotein levels resulting from estrogen replacement therapy account for only
25% to 50% of the observed risk reduction, suggesting that additional factors
are involved.25 Cardio-protective mechanisms unrelated to lipid lowering
also evident in women with heterozygous familial hypercholesterolemia.26 Despite
higher levels of total and LDL cholesterol, these (mostly young) women have a
reduced incidence and a markedly delayed onset of the clinical manifestations
of coronary disease compared with their male counterparts.
modifies directly the functions of the endothelium and vascular smooth muscle. In health, the vascular
endothelium provides a surface that is vasodilatory, anticoagulant, and
anti-adhesive for leukocytes and that inhibits proliferation of vascular smooth
muscle cells.27 Although discovered as an endothelium-derived vasodilator
factor,28 nitric oxide may retard atherogenesis by inhibiting
adhesion,29 30 synthesis of factors chemotactic for monocytes,31 smooth muscle cell proliferation,32 and platelet aggregation.33 34 Experimental and clinical studies suggest that dysfunctional
endothelium in atherosclerosis or in the presence of risk factors loses these
favorable effects.27 35 36 37 38 39 The impact of estrogen deficiency on the endothelium
evaluated by observing endothelial function following replacement of estrogen.
In these studies, estrogen enhances endothelium-dependent vasodilation in normo-cholesterolemic
ovariectomized animals as well as in ovarie-ctomized monkeys with dietary
atherosclerosis.3 40 41 This improvement is associated with augmentation of
and vasodilator prostaglandin levels.
Estrogen replacement therapy also corrects coronary
endothelium-dependent vasodilation in postmenopausal women with
atherosclerosis. Intravenous administration of 17β-estradiol, conjugated
estrogens, and ethinyl estradiol rapidly improves coronary responses to
acetylcholine.42 43 44 45 Long-term estrogen replacement restores coronary responses
acetylcholine in monkeys with dietary atherosclerosis and augments
endothelium-dependent dilation in hypercholesterolemic, postmenopausal women.3 46 Serum nitrate and nitrite levels are higher in postmenopausal
women receiving long-term estrogen
replacement, suggesting enhanced production of nitric oxide.47
The molecular mechanisms by which estrogen replacement modulates
endothelial function are not well defined. Steroid hormones such as estrogen
bind to highly specific cytoplasmic receptors.48 They form a mobile cytoplasmic steroid-receptor complex
ultimately translocates to the nucleus and binds directly to nonhistone
proteins on the DNA to activate transcription of genes. Long-term
administration of estrogen upregulates the transcription of nitric oxide
synthase and enhances its activity in nonvascular tissue.49 Whether such upregulation occurs in vascular tissues
determined. It is unlikely that acute improvement in endothelium-dependent
vasodilation, observed in as little as 15 minutes, can be explained by this
classic steroid-hormone receptor interaction.4243 44 45 Receptor-independent mechanisms, such as the ability
to act as an antioxidant, have therefore been postulated to account for the
rapid restoration of endothelium-dependent vasodilation.50
Treatment with a number of antioxidant agents restores
endothelium-dependent vasodilation in atherosclerosis. Impairment of
endothelium-dependent vasodilation in atherosclerosis is related in part to
increased production of oxygen-derived free radicals.51 Oxygen-derived free radicals can directly inactivate
oxide in the vascular wall, as well as indirectly damage endothelium by
oxidizing LDL particles.52 53 54 Estrogens
possess antioxidant activity related to the presence of a phenolic ring, eg, in estriol and 17β-estradiol.55 When estradiol is administered to ovariectomized swine
dietary atherosclerosis, endothelium-dependent vasorelaxation is restored in
conjunction with evidence of protection
of LDL from oxidation.50 Susceptibility of LDL to oxidation is also reduced
postmenopausal women taking replacement estrogen.56 The observed rapid benefit of estrogen cannot be explained
reduced LDL oxidation and would require that estrogen decrease oxygen-derived
free radicals directly in the arterial wall.
Changes in the vasculature following estrogen replacement are
not confined to the endothelium and may involve vascular smooth muscle,
extracellular matrix, and the formation of collaterals. Estrogen modulates the
reactivity of vascular smooth muscle. Contraction of vascular smooth muscle in
response to the administration of endothelin 1 or the calcium channel agonist
BAY K 8644 is inhibited by estrogen treatment in animals.57 58 Estrogen increases potassium conductance in vascular
muscle, a change that would favor vasodilation.59 Extracellular matrix composition may be modified by
therapy, affecting its contribution to vessel wall stability.60 For example, estradiol treatment changes the proportion
collagen and elastin and the ratio of procollagen type I to procollagen type
III in blood vessels.61 62 63 The impact
of these findings on the vulnerability of atherosclerotic plaques to rupture
must be established. The
enlargement of preexistent collateral channels in the presence of a severe
stenosis is likely to lessen the impact of a subsequent coronary occlusion.64 65 66 67 Formation of collaterals involves transformation of
collaterals to mature collaterals through a process of vascular remodeling.68 Under in vitro conditions, estrogen treatment enhances
and proliferation of endothelial cells and facilitates their organization into
tubular networks, steps that are critical to angiogenesis.69In vivo models have demonstrated that estrogen potentiates the
angiogenic effect of fibroblast growth factor. The applicability of these
findings in patients with clinical coronary disease must be investigated.
In this issue of Circulation,
Collins and colleagues70 report that coronary vasodilation to acetylcholine
20 minutes after administration of 17β-estradiol in postmenopausal women with
coronary disease but not in men. This unexpected finding of a gender-specific
benefit suggests that the rapid improvement in endothelial function cannot be
accounted for by the proposed receptor-independent actions of estrogen and that
estrogen receptors are required. The males in this study presumably have fewer
estrogen receptors than the females, accounting for a lack of effect.
Interestingly, estrogen can upregulate its own receptors,71 permitting
males to respond. Estrogen increases transcription of nitric oxide synthase in
male guinea pigs, but with a marked delay compared with females.49 This lag phase may be due to upregulation of estrogen
needed in male guinea pigs. The findings of the study by Collins et al could be
explained by a novel interaction of estrogen with its steroid receptor. This
hormone-receptor complex could activate nontranscriptional signaling events in
the cytoplasm, resulting in prompt improvement in endothelium-dependent
Actions of estrogen have been elucidated that tend to correct
the characteristic disturbances associated with the biology of atherosclerosis.
Resorption of extracellular lipid as a
result of improvement in lipoprotein metabolism and reversal of endothelial
dysfunction may be particularly important effects of estrogen, expected to
retard atherogenesis and enhance the stability of existing plaques. As this
study by Collins et al70 points out, the molecular basis of improvement in
function is not yet clearly understood. The intriguing findings of this study
force us to rethink our views of the mechanisms by which estrogen improves
endothelium-dependent vasodilation and should stimulate new directions in
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