title: Estrogen modulates AT1 receptor gene expression in vitro and in vivo.
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.
  
  
  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 micromol/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.
authors.affiliation: Klinik III für Innere Medizin, Universität zu Köln, Germany. georg.nickenig@uni-koeln.de
authors.forename: G
authors.initials: G
authors.lastname: Nickenig
authors.forename: A T
authors.initials: AT
authors.lastname: Bäumer
authors.forename: C
authors.initials: C
authors.lastname: Grohè
authors.forename: S
authors.initials: S
authors.lastname: Kahlert
authors.forename: K
authors.initials: K
authors.lastname: Strehlow
authors.forename: S
authors.initials: S
authors.lastname: Rosenkranz
authors.forename: A
authors.initials: A
authors.lastname: Stäblein
authors.forename: F
authors.initials: F
authors.lastname: Beckers
authors.forename: J F
authors.initials: JF
authors.lastname: Smits
authors.forename: M J
authors.initials: MJ
authors.lastname: Daemen
authors.forename: H
authors.initials: H
authors.lastname: Vetter
authors.forename: M
authors.initials: M
authors.lastname: Böhm
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010052:Ovariectomy; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D011921:Rats, Inbred WKY; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D004967:Estrogens; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D004958:Estradiol