Differential effects of estrogen and progesterone on AT(1) receptor gene expression in vascular smooth muscle cells

Abstract

Background: The beneficial vasoprotective effects of a postmenopausal estrogen replacement therapy may be prevented by a concomitant administration of progestins. To investigate the differential effects of estrogens and progesterone, we examined their influence on AT(1) receptor gene expression in vascular smooth muscle cells (VSMCs).

Methods and results: 17beta-Estradiol caused downregulation of AT(1) receptor mRNA expression to 46+/-14%, whereas progesterone led to a significant upregulation to 201+/-29%, as assessed by Northern analysis. Western blots revealed that estrogen induced a downregulation and progesterone an upregulation of the AT(1) receptor protein. Estrogen-induced decrease of AT(1) receptor expression was mediated through activation of estrogen receptors. Nuclear run-on assays revealed that 17beta-estradiol did not alter AT(1) receptor mRNA transcription rate, whereas progesterone caused an enhanced AT(1) receptor mRNA transcription rate. 17beta-Estradiol decreased the AT(1) receptor mRNA half-life from 5 to 2 hours, whereas progesterone induced a stabilization of AT(1) receptor mRNA to a half-life of 10 hours. Preincubation of VSMCs with PD98059, SB203580, herbimycin, wortmannin, or N:(omega)-nitro-L-arginine suggested that 17beta-estradiol caused AT(1) receptor downregulation through nitric oxide-dependent pathways. Progesterone caused AT(1) receptor overexpression via PI(3)-kinase activation. Angiotensin II-induced release of reactive oxygen species was inhibited by estrogens. Progesterone itself enhanced the production of reactive oxygen species.

Conclusions: Because AT(1) receptor regulation plays a pivotal role in the pathogenesis of hypertension and atherosclerosis, the differential effects of estrogen and progesterone on the expression of this gene may in part explain the potentially counteracting effects of these reproductive hormones on the incidence of postmenopausal cardiovascular diseases.