Abstract
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 E(2) 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 ERalpha or ERbeta and treated with 100 nm 17beta-estradiol (E(2)) for 24 h. E(2) treatment decreased basal luciferase activity by 51%, and this effect was dependent on co-expression of ERalpha, whereas no repression was observed with ERbeta. A mutation within the DNA binding domain of the ERalpha abolished the repressor function of the ER receptor. Similarly, E(2) decreased IGF-1R transcription by 21% in rat aortic smooth muscle cells (RASMC), which express endogenous ER. This effect was specific for E(2), 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, E(2) decreased IGF-1R and IGF-1 mRNA in RASMC by 47% and 33%. Western blot analysis and radioligand binding studies showed that E(2) 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 ERalpha and E(2) 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, E(2) 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.
Highlights
Insulin-like growth factor (IGF-1) is a potent mitogen for vascular smooth muscle cells
E2 decreased IGF-1 receptor (IGF-1R) transcription by 21% in rat aortic smooth muscle cells (RASMC), which express endogenous estrogen receptors (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
The fact that E2 stimulated transactivation of a minimal estrogen response elements (ERE) promoter reporter construct in RASMC without transfecting HEG0 supports the notion that the endogenous ERs were functional as has been previously shown by others [41]
Summary
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. Direct effects of estrogens have been demonstrated in vitro and in vivo both in animal and human models These include effects on gene expression [7, 8], ion channel function [9, 10], response to vasoactive substances [11,12,13,14], as well as vascular smooth muscle cell proliferation and migration [14, 15]. These data indicate that ER can modulate transcription from promoters that lack classical estrogen response elements (ERE) and have important implications for understanding cardiovascular effects of estrogens
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