From the Klinik III für Innere Medizin, Universität zu
Köln (G.N., A.T.B., K.S., S.R., A.S., F.B., M.B.), and the Medizinische
Universitäts-Poliklinik, Bonn (C.G., S.K., H.V.), Germany; and the
Departments of Pharmacology (J.F.M.S.) and Pathology (M.J.A.P.D.),
Cardiovascular Research Institute, University of Maastricht, the Netherlands.
Drs Nickenig and Bäumer contributed equally to this study.
Correspondence to Dr Georg Nickenig, Klinik III für Innere Medizin, Joseph-Stelzmann-Str 9, 50924 Köln, Germany. E-mail georg.nickenig{at}uni-koeln.de
Abstract
Background—The AT1
receptor has been implicated in the pathogenesis of hypertension and
atherosclerosis. Estrogen deficiency is also associated
with cardiovascular diseases. Therefore, we examined
the AT1 receptor gene expression in ovariectomized rats
with and without estrogen replacement therapy and the influence of
estrogen on AT1 receptor expression in cultured vascular
smooth muscle cells.
Methods and Results—Rat aortic tissue was examined 5 weeks after
ovariectomy. In one group, estrogen (1.7 mg estradiol) was administered
during the 5-week period. Functional experiments assessed
angiotensin II–induced contraction of aortic rings.
AT1 receptor mRNA levels were measured by quantitative
polymerase chain reaction and Northern blotting. AT1
receptor density was assessed by radioligand binding
assays. These techniques were also applied in cultured vascular smooth
muscle cells. The efficacy of angiotensin II on
vasoconstriction was significantly increased in aortas from
ovariectomized rats. As assessed by radioligand binding
assays, AT1 receptor density was increased to 160% without
changes in receptor affinity during estrogen deficiency.
AT1 receptor mRNA levels were consistently
increased to 187% in ovariectomized rats compared with sham-operated
animals. Estrogen substitution therapy in ovariectomized rats reversed
this AT1 receptor overexpression. To explore the underlying
mechanisms, the direct influence of estradiol on AT1
receptor expression was investigated in VSMCs. Estradiol (1
µmol/L) led to a time-dependent downregulation of AT1
receptor mRNA, with a maximum of 33.3% at 12 hours. There was a
correlative decrease in AT1 receptor density.
Conclusions—This novel observation of estrogen-induced
downregulation of AT1 receptor expression could explain the
association of estrogen deficiency with hypertension and
atherosclerosis, because activation of the
AT1 receptor plays a key role in the regulation of blood
pressure, fluid homeostasis, and vascular cell growth.
© 1998 American Heart Association, Inc.
Brief Rapid Communication
Estrogen Modulates AT1 Receptor Gene Expression In Vitro and In Vivo
Key Words: angiotensin • hypertension • hormones • genes • muscle, smooth • atherosclerosis
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