Estrogen Signaling through Estrogen Receptor Beta and G-Protein-Coupled Estrogen Receptor 1 in Human Cerebral Vascular Endothelial Cells: Implications for Cerebral Aneurysms

Figure 6

Hypothetical estrogen signaling pathways in human cerebral vascular endothelial cells. 17β-Estradiol (E2) passes through plasma and nuclear membranes activate nuclear ERβ through 3 mechanisms. First mechanism: 17β-estradiol causes ERβ dimerization, binds the ERβ dimer to the promoter of the estrogen-responsive gene, phosphorylation (P) of ERβ, and transcriptionally regulates the estrogen-responsive gene. The active genes produce mRNA molecules, which guide the synthesis of specific proteins. These proteins can then influence the behaviour of HCVECs. Second mechanism: activated ERβ modulates the function of transcription factors (TF) through protein-protein interactions. Third mechanism: 17β-estradiol (E2) binds to ERβ at the plasma membrane (mER). This estrogen-ERβ complex binds to adaptor 1 (Adaptor) protein and the signaling molecule such as c-Src, which mediates rapid signaling via PI3K-Akt and MAPK pathway to activate the promoter region of estrogen-responsive genes. Alternatively, 17β-estradiol (E2) passes through plasma, binds to GPER1 (GPER), and activates c-Src. c-Src activates matrix metalloproteinase (MMP). MMP cleaves pro-heparin-binding-epidermal growth factor (pro-HB-EGF) that transactivates epidermal growth factor receptor (EGFR). EGFR activates phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) and mitogen-activated protein kinase (MAPK) pathway. 17β-Estradiol (E2) GPER complex also activates cAMP production to restore EGF-activated MAPK to basal levels through protein kinase A (PKA) dependent inhibition of Raf-1 activity. Akt: protein kinase B; c-Src: protooncogene tyrosine-protein kinase Src; E2: 17β-estradiol; ER: estrogen receptor beta and/or G-protein-coupled estrogen receptor-1; EGFR: epidermal growth factor receptor; GPER: G-protein-coupled ER; MAPK: mitogen-activated protein kinase; mER: plasma membrane ER; MMP: matrix metalloproteinase; P: phosphorylation; PI3K: phosphatidylinositol 3-kinase; PKA: protein kinase A; pro-HB-EGF: pro-heparin-binding-epidermal growth factor; Raf-1: RAF protooncogene serine/threonine-protein kinase; TF: transcription factors. JT modified the image by permission from Macmillan Publishers Ltd. Nature Reviews Endocrinology [17]. Copyright 2011 to Jian Tu for reuse of the original image from Nature Publishing Group (the original image is available in colour at http://www.nature.com/nrendo/index.html).