Estrogen signaling and cardiovascular disease

Abstract

Estrogen has pleiotropic effects on the cardiovascular system. The mechanisms by which estrogen confers these pleiotropic effects are undergoing active investigation. Until a decade ago, all estrogen signaling was thought to occur by estrogen binding to nuclear estrogen receptors (estrogen receptor-α and estrogen receptor-β), which bind to DNA and function as ligand-activated transcription factors. Estrogen binding to the receptor alters gene expression, thereby altering cell function. Estrogen also binds to nuclear estrogen receptors that are tethered to the plasma membrane, resulting in acute activation of signaling kinases such as PI3K. An orphan G-protein-coupled receptor, G-protein-coupled receptor 30, can also bind estrogen and activate acute signaling pathways. Thus, estrogen can alter cell function by binding to different estrogen receptors. This article reviews the different estrogen receptors and their signaling mechanisms, discusses mechanisms that regulate estrogen receptor levels and locations, and considers the cardiovascular effects of estrogen signaling.

Figure 1

Figure 1 shows the major mechanism by which ER can alter gene expression. Estrogen (E2) binds to ER resulting in dimerization and recruitment of co-regulators (not shown due to space limitations). The estrogen-ER complex binds to estrogen response elements (ERE) on the DNA resulting in altered gene transcriptions. Estrogen can also alter gene transcription by binding to transcription factors (TF) such as AP1. In addition, ER can be phosphorylated by growth factors and other plasma membrane estrogen receptors that are coupled to kinase signaling. Phosphorylated ER can activate gene transcription in a ligand-independent manner.

Figure 2

Figure 2 A illustrated the interaction of the genomic and acute estrogen signaling pathways in regulating nitric oxide (NO) signaling. Estrogen (E2) can bind to ER resulting in dimerization and activation of gene transcription. Nitric oxide synthase (NOS) expression has been reported to be regulated by E2 and females have been shown to have higher levels of NOS than males. In addition, E2 active via rapid signaling pathways can activate the PI3K pathway regulating in phosphorylation and activation of NOS. Figure 2B illustrates how this signaling might be altered with aging and disease and provides a possible explanation as to why HRT failed to protect in post-menopausal women. Tetrahydropterin (BH4) is a cofactor for NOS and in the absence of BH4, NOS now generates ROS rather than NO.

Figure 3

Figure 3 illustrated the different mechanisms that can regulate the level and activity of ER. ER expression is regulated by methylation of the ER promoter region. In many cell types estrogen has been shown to increase ERa transcription and progesterone, vitamin D and ERα36 have been reported to decrease expression of ER. ER transcriptional activity can be regulated by post-translational modifications such as acetylation (Ac), which activates transcriptional activity or by S-nitrosylation (SNO) which tends to inhibit translational activity.