Rapid progress for non-nuclear estrogen receptor signaling

Abstract

Estrogen receptors are best known as ligand-activated transcription factors that regulate vascular cell gene expression. For many years now, a rapid signaling pathway mediated by cell membrane-associated estrogen receptors also has been recognized, but the physiological relevance of this pathway has remained unclear. In this issue of the JCI, Chambliss et al. provide new data to indicate that activation of non-nuclear estrogen receptor signaling regulates processes central to cardiovascular health and disease. These investigators show that an estrogen-dendrimer conjugate (EDC), which activates estrogen receptors but remains non-nuclear, stimulates vascular EC migration in vitro and protects against vascular injury in vivo. They show further that the vascular benefits of EDC in vivo occur selectively in the vasculature, without stimulating the uterus or enhancing growth of breast cancer xenografts. Taken together, these findings indicate that activation of non-nuclear estrogen receptor signaling regulates vascular events of physiological relevance and suggest that translation of these findings into clinically relevant therapeutic interventions is a logical next goal.

Figure 1. ER signaling pathways in vascular ECs.

ERs are ligand-activated transcription factors that translocate to the nucleus upon estrogen binding and regulate gene expression. Classically, the hormone-bound receptor dimerizes and binds to specific DNA sequences called estrogen response elements (ERE), displacing corepressors (CoR) from the DNA, recruiting coactivator (CoA) proteins, and activating gene expression. ERs can also be transcriptionally activated via ligand-independent pathways in which growth factor receptor (GFR) activation leads to activation of specific kinases that directly phosphorylate the ER, again leading to altered gene expression, either directly by the ER or via ER interactions with other transcription factors (TFs). In the current issue of the JCI, Chambliss and colleagues demonstrate the in vivo importance of a long-recognized third signaling pathway mediated by non-nuclear ERs in ECs (6). In this pathway, estrogen induces a subpopulation of cell membrane–associated ERs to form a signaling complex that results in rapid activation of specific kinases, which in turn phosphorylate and enzymatically activate eNOS.

Figure 2. Non-nuclear ER signaling in vascular EC caveolae.

A subpopulation of non-nuclear ERs localize to EC plasma membrane invaginations called caveolae by direct binding to caveolar proteins, including the scaffold protein striatin, which is bound to the major caveolar structural protein, caveolin-1 (Cav-1). Upon estrogen binding, signaling complexes assemble that include ERs and the G protein G_αi and sequentially activate the tyrosine kinase src, the serine/threonine kinase PI3K that produces phosphatidylinositol (3,4,5)-triphosphate (PIP₃), and the kinase Akt. Akt then directly phosphorylates eNOS on serine 1,177, leading to its enzymatic activation and production of NO. Whether the ERs are apposed to the inner leaflet of the plasma membrane, or are somehow localized on the external face of the membrane, remains unclear. In the current issue of the JCI, Chambliss and coworkers demonstrate that in vivo activation of this non-nuclear ER-dependent pathway by EDC confers protection against vascular injury in the mouse (6).