Estradiol decreases IGF-1 and IGF-1 receptor expression in rat aortic smooth muscle cells - Mechanisms for its atheroprotective effects

Insulin-like growth factor (IGF-1) is a potent mitogen for vascular smooth muscle cells, Both IGF-1 and its receptor have been shown to be highly expr essed in atherosclerotic lesions. Here we investigated whether part of the vasculoprotective properties of E-2 may be mediated by its negative regulat ion of the IGF-1 system. HeLa cells, which do not contain endogenous estrog en receptors (ER), were transiently 'transfected with IGF-1R promoter const ructs with or without a plasmid encoding human ER alpha or ER beta and trea ted with 100 nM 17 beta -estradiol (E-2) for 24 h. E-2 treatment decreased basal luciferase activity by 51%, and this effect was dependent on co-expre ssion of ER alpha, whereas no repression was observed with ER beta. A mutat ion within the DNA binding domain of the ER alpha abolished the repressor f unction of the ER receptor. Similarly, E-2 decreased IGF-1R transcription b y 21% in rat aortic smooth muscle cells (RASMC), which express endogenous E R, This effect was specific for E-2, because it was inhibited by an antiest rogen and because progesterone did not have any effect on IGF-1R expression in HeLa or RASMC transfected with progesterone receptor. Accordingly, E-2 decreased IGF-1R and IGF-1 mRNA in RASMC by 47% and 33%, Western blot analy sis and radioligand binding studies showed that E-2 also dose-dependently d ecreased IGF-1R protein expression in RASMC by 40% and 30%, respectively, a nd that IGF-1 protein was reduced by 43%. Repression of IGF-1R promoter act ivity by a combination of ER alpha and E-2 did not appear to be mediated vi a direct binding of ER to the IGP-1R promoter but rather by inhibition of S P1 binding to the IGF-1R promoter. Thus, E-2 down-regulates IGF-1R and IGF- 1 expression in vascular smooth muscle cells, This may have important impli cations for the understanding of the beneficial effects of estrogen in the cardiovascular system.