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J. Biol. Chem., Vol. 275, Issue 49, 38921-38928, December 8, 2000

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Estradiol Decreases IGF-1 and IGF-1 Receptor Expression in Rat Aortic Smooth Muscle Cells
MECHANISMS FOR ITS ATHEROPROTECTIVE EFFECTS^*

Kathrin J. Scheidegger, Bruno Cenni^§, Didier Picard^§, and Patrick Delafontaine^¶

From the  Division of Cardiology, University Hospital of Geneva, 1211 Geneva 14, Switzerland and the ^§ Department of Cell Biology, University of Geneva, 1211 Geneva 4, Switzerland

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 expressed in atherosclerotic lesions. Here we investigated whether part of the vasculoprotective properties of E₂ may be mediated by its negative regulation of the IGF-1 system. HeLa cells, which do not contain endogenous estrogen receptors (ER), were transiently transfected with IGF-1R promoter constructs with or without a plasmid encoding human ER or ER and treated with 100 nM 17-estradiol (E₂) for 24 h. E₂ treatment decreased basal luciferase activity by 51%, and this effect was dependent on co-expression of ER, whereas no repression was observed with ER. A mutation within the DNA binding domain of the ER abolished the repressor function of the ER receptor. Similarly, E₂ decreased IGF-1R transcription by 21% in rat aortic smooth muscle cells (RASMC), which express endogenous ER. This effect was specific for E₂, because it was inhibited by an antiestrogen and because progesterone did not have any effect on IGF-1R expression in HeLa or RASMC transfected with progesterone receptor. Accordingly, E₂ decreased IGF-1R and IGF-1 mRNA in RASMC by 47% and 33%. Western blot analysis and radioligand binding studies showed that E₂ also dose-dependently decreased IGF-1R protein expression in RASMC by 40% and 30%, respectively, and that IGF-1 protein was reduced by 43%. Repression of IGF-1R promoter activity by a combination of ER and E₂ did not appear to be mediated via direct binding of ER to the IGF-1R promoter but rather by inhibition of SP1 binding to the IGF-1R promoter. Thus, E₂ down-regulates IGF-1R and IGF-1 expression in vascular smooth muscle cells. This may have important implications for the understanding of the beneficial effects of estrogen in the cardiovascular system.

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