Non-nuclear Estrogen Receptor Signaling in the Endothelium

Philip W. Shaul,Chieko Mineo,Michihisa Umetani,Qian Wu,Ken Chambliss

doi:10.1074/jbc.r110.191791

Philip W. Shaul, Chieko Mineo + Show 3 more

Open Access

https://doi.org/10.1074/jbc.r110.191791

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Abstract

In addition to the classical function of estrogen receptors (ER) as transcription factors, evidence continues to accumulate that they mediate non-nuclear processes in numerous cell types, including the endothelium, in which they activate endothelial NO synthase. Non-nuclear ER signaling entails unique post-translational modifications and protein-protein interactions of the receptor with adaptor molecules, kinases, and G proteins. Recent in vitro and in vivo studies in mice using an estrogen-dendrimer conjugate that is excluded from the nucleus indicate that non-nuclear ER activation underlies the migration and growth responses of endothelial cells to estrogen but not the growth responses of endometrial or breast cancer cells to the hormone. In this minireview, the features of ERα and protein-protein interactions that enable it to invoke extranuclear signaling in the endothelium and the consequences of that signaling are discussed.

Highlights

In addition to the classical function of estrogen receptors (ER) as transcription factors, evidence continues to accumulate that they mediate non-nuclear processes in numerous cell types, including the endothelium, in which they activate endothelial NO synthase
Along with these actions that involve the classical functions of ER as transcription factors, short-term effects of estrogen on the vasculature were demonstrated in humans, and they provided the initial suggestion that there are non-nuclear actions of the hormone and its receptors
The studies in mice using estrogen-dendrimer conjugate (EDC) revealed that non-nuclear ER␣ coupling to G␣i is operative in vivo, and a beneficial impact on neointima formation has been demonstrated

Summary

Endothelial Actions of Estrogen

Estrogen has potentially potent cardiovascular protective actions, and these are primarily through direct effects on endo-. In endothelial cells in culture, estrogen up-regulates the expression of endothelial NO synthase (eNOS) [4], cyclooxygenase-1 [8], MMP-2 [9], and ER␣ [10], and it blunts the expression of endothelin [11] and the type 1 angiotensin II receptor [12] Along with these actions that involve the classical functions of ER as transcription factors, short-term effects of estrogen on the vasculature were demonstrated in humans, and they provided the initial suggestion that there are non-nuclear actions of the hormone and its receptors. MINIREVIEW: Non-nuclear ER Signaling in the Endothelium coupling to eNOS in isolated plasma membranes provided additional clarity of membrane receptor identity, with immunoidentification studies directed at multiple epitopes detecting the same 67-kDa ER␣ protein and the same 54-kDa ER␤ protein in purified plasma membrane fractions and in the nucleus [22, 23]. Classical ER␣ and ER␤, and perhaps truncated forms of ER␣ (i.e. ER␣46), mediate the non-nuclear actions of the hormone in endothelial cells

ER Localization to Plasma Membrane Microdomains

Conclusions and Current Questions