Estrogen Receptor Null Mice - Endocrine Reviews
Estrogen Receptor Null Mice - Endocrine Reviews
Estrogen Receptor Null Mice - Endocrine Reviews
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June, 1999 ESTROGEN RECEPTOR NULL MICE 399<br />
also be true in the �ERKO male, which exhibit slightly<br />
shorter femur lengths in the context of only a 2-fold increase<br />
in serum androgens. The possibility that a loss of ER� during<br />
bone development results in abnormal genomic imprinting<br />
and increased ER� and/or AR levels as a compensatory<br />
mechanism must also be considered.<br />
B. Cardiovascular system<br />
Since the early part of this century, a remarkable genderrelated<br />
contrast in the risk of cardiovascular disease has been<br />
known. Although women generally possess a greater incidence<br />
of the multiple risk factors associated with cardiovascular<br />
disease when compared with men, e.g., obesity, diabetes,<br />
elevated blood pressure, and plasma cholesterol,<br />
epidemiological studies continue to indicate their relative<br />
risk of developing this disease is significantly lower (453,<br />
454). It is now believed that the protective factor against<br />
cardiovascular disease in females is their inherently increased<br />
exposure to estrogens (reviewed in Refs. 433 and<br />
454). The protective effects of estrogens have been documented<br />
in a number of epidemiological studies documenting<br />
the reduced rate of cardiovascular disease in postmenopausal<br />
women receiving estrogen replacement therapy (433,<br />
454). This correlation between the administration of estradiol<br />
and a reduced risk of vascular disease has been reproduced<br />
in laboratory animal studies involving several different species<br />
(454).<br />
The possible mechanisms by which estrogens reduce vascular<br />
disease remain unclear but are likely to include positive<br />
modifications of a number of physiological parameters that<br />
are believed to impinge upon the development of cardiovascular<br />
pathlogy (reviewed in Ref. 454). Most notable of<br />
these is the ability of estrogen replacement therapy to significantly<br />
lower total cholesterol, with a profound effect on<br />
levels of the more damaging low-density lipoproteins (LDLs)<br />
(454). Hypercholesterolemia is strongly associated with the<br />
development of cardiovascular disease. The ability of estrogen<br />
therapy to reduce total cholesterol levels is believed to<br />
account for a large portion of the cardiovascular protective<br />
effects of the hormone (433, 454). Lundeen et al. (455) reported<br />
that the significant decreases in serum cholesterol are<br />
specific to estrogen action in the ovariectomized rat, whereas<br />
other gonadal steroids tested had little effect. Furthermore,<br />
cotreatment with the antagonist, ICI-182,780, was shown to<br />
inhibit the cholesterol-lowering effects of estrogens, strongly<br />
indicating that this is a receptor-mediated effect (455). One<br />
possible site at which the actions of estradiol may converge<br />
with the pathways of cholesterol metabolism is via the upregulation<br />
of the apo E protein and the apolipoprotein (apo)<br />
B/E LDL receptor within and on the cell surface of hepatocytes,<br />
respectively (454). During hydrolysis of triglycerides<br />
in the circulation, the apo E protein is integrated into the apo<br />
B-LDL complexes and thereby functions as a ligand for the<br />
hepatocyte apo B/E LDL receptor (454). When the apo Econtaining<br />
LDL complex is bound by the apo B/E LDL receptor<br />
on the cell surface of hepatocytes, the complex is<br />
internalized, thereby providing for a means of clearing LDL<br />
from the blood (454). The importance of the apo E protein in<br />
maintaining serum cholesterol levels and providing protec-<br />
tion against vascular disease is evident from studies in transgenic<br />
mice that either overexpress the protein or possess a<br />
targeted disruption of the apo E gene. Transgenic mice in<br />
which an apo E gene is overexpressed are significantly protected<br />
from atherosclerosis (456), whereas the apo E knockout<br />
is highly susceptible to the vascular disease (457).<br />
Therefore, much of the cholesterol-lowering ability of estradiol<br />
is thought to be due to increased clearance of LDL<br />
from the circulation via the mechanism described above<br />
(454). Regulation of the apo E gene by estradiol has been<br />
demonstrated in the rat (458, 459). Furthermore, Srivastava<br />
et al. (460) recently reported that hepatic levels of apo E<br />
mRNA are similar in wild-type and �ERKO male littermates,<br />
although a slight decrease in serum levels of the protein was<br />
observed in the �ERKO. However, 6 days of estradiol exposure<br />
(via implantation of a 3 �g E 2/g body weight/day<br />
pellet) elicited an almost 2-fold increase in serum apo E levels<br />
in the wild-type compared with a 1.2-fold increase in the<br />
�ERKO (460). Therefore, these data provide evidence that<br />
ER�, acting at the level of translation, is required to mediate<br />
the estradiol up-regulation of apo E expression in mice (460).<br />
In addition to the favorable effects of estrogens on the lipid<br />
profile, it is now believed the steroid may also play a beneficial<br />
function directly at the level of the vasculature. The<br />
proposed mechanisms of estrogen action on the vasculature<br />
include modulations of vascular adhesion molecules, chemoattractants,<br />
vasodilators (e.g., nitric oxide), vasoconstrictors<br />
(e.g., endothelin-1), as well as possibly acting as an antioxidant<br />
(reviewed in Refs. 454 and 461). Several of the<br />
effects of estrogens, as well as other steroid hormones, on<br />
blood vessel physiology have been proposed to be nongenomic<br />
and independent of the classical nuclear activational<br />
pathway of steroid receptors (reviewed in Ref. 355).<br />
However, ER has been detected in both the endothelial and<br />
smooth muscle cells of the vasculature in several species,<br />
suggesting a role for receptor-mediated actions as well (reviewed<br />
in Refs. 431, 454, and 462). Furthermore, a recent<br />
study reported that the level of ER in atherosclerotic plaques<br />
from human coronary arteries was reduced compared with<br />
levels found in nonlesioned sections (463). Studies have indicated<br />
the presence of ER� in the vasculature as well. Analysis<br />
by ribonuclease protection assay for ER� and ER�<br />
mRNA in the mouse indicate only detectable levels of ER�<br />
transcripts in the aorta (93). However, Iafrati et al. (464) report<br />
the detection of ER� transcripts by RT-PCR in mouse aorta<br />
and blood vessels, including those of the �ERKO. The apparent<br />
contrast in ER� detection between these two reports<br />
in the �ERKO vasculature is most likely due to differences<br />
in the sensitivity of the techniques used, since ER� mRNA<br />
was detected only by the more sensitive RT-PCR method.<br />
This is likely a reflection of the low levels of this receptor<br />
compared with ER�. In the rat aorta, Petersen et al. (70)<br />
described the detection of full-length and variant ER�<br />
mRNA by RT-PCR. Recent reports also describe the detection<br />
of ER� transcripts by RT-PCR in aortic smooth muscle cells<br />
and coronary artery (465), aorta, and cardiac muscle (96)<br />
from monkey. An intriguing report of the tissue distribution<br />
for ER� and ER� mRNA in human vasculature was that of<br />
Tschugguel et al., which described the presence of ER�<br />
mRNA only in cultures from larger blood vessels, i.e., aorta