ESTROGEN MODULATES AT(1) RECEPTOR GENE-EXPRESSION IN-VITRO AND IN-VIVO

Background-The AT(1) receptor has been implicated in the pathogenesis of hypertension and atherosclerosis, Estrogen deficiency is also assoc iated with cardiovascular diseases. Therefore, we examined the AT(1) r eceptor gene expression in ovariectomized rats with and without estrog en replacement therapy and the influence of estrogen on AT(1) receptor expression in cultured vascular smooth muscle cells. Methods and Resu lts-Rat aortic tissue was examined 5 weeks after ovariectomy. In one g roup, estrogen (1.7 mg estradiol) was administered during the 5-week p eriod. Functional experiments assessed angiotensin II-induced contract ion of aortic rings. AT(1) receptor mRNA levels were measured by quant itative polymerase chain reaction and Northern blotting. AT(1) recepto r density was assessed by radioligand binding assays. These techniques were also applied in cultured vascular smooth muscle cells. The effic acy of angiotensin II on vasoconstriction was significantly increased in aortas from ovariectomized rats, As assessed by radioligand binding assays, AT(1) receptor density was increased to 160% without changes in receptor affinity during estrogen deficiency. AT(1) receptor mRNA l evels were consistently increased to 187% in ovariectomized rats compa red with sham-operated animals. Estrogen substitution therapy in ovari ectomized rats reversed this AT1 receptor overexpression, To explore t he underlying mechanisms, the direct influence of estradiol on AT(1) r eceptor expression was investigated in VSMCs, Estradiol (1 mu mol/L) l ed to a time-dependent downregulation of AT(1) receptor mRNA, with a m aximum of 33.3% at 12 hours. There was a correlative decrease in AT(1) receptor density. Conclusions-This novel observation of estrogen-indu ced downregulation of AT(1) receptor expression could explain the asso ciation of estrogen deficiency with hypertension and atherosclerosis, because activation of the AT(1) receptor plays a key role in the regul ation of blood pressure, fluid homeostasis, and vascular cell growth.