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The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System

The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System

Sara Menazza, Elizabeth Murphy

Nongenomic estrogen receptor (ER) signaling. A, Rapid ER signaling in vascular endothelial cells. ERs localize to caveolae by direct binding to caveolin-1 and scaffold protein striatin. On estrogen binding, ERs and the G protein form a complex leading to activation of tyrosine kinase Src, serine/threonine kinase phosphatidylinositol-3-OH kinase (PI3K; binding the subunit p38a), activation of protein kinase B (Akt), and mitogen-activated protein kinase (MAPK). Kinases then directly activate endothelial nitric oxide synthase (eNOS) by serine 1177 phosphorylation. The increased production of nitric oxide (NO) promotes endothelial cell vasodilatation, proliferation, and migration. B, Rapid ER signaling in vascular smooth muscle cells. ERs localize to caveolae by direct binding to caveolin-1 and scaffold protein striatin. On estrogen binding, ERs activate several phosphatases leading to inhibition of kinases and finally resulting in a decrease of cell proliferation and migration. MKP-1 indicates mitogen-activated protein kinase phosphatase-1; PP2A, protein phosphatase 2A; PTEN, phosphatase and tensin homolog; and SHP-1, Src homology region 2 domain-containing phosphatase-1. [Powerpoint File]

The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System

The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System

Sara Menazza, Elizabeth Murphy

Effects of estrogen on the heart. Estrogen has many pleiotropic effects on the cardiovascular system. Estrogen can impact cardiovascular health and disease by direct effects: (1) on the vascular endothelial cells promoting vasorelaxation, cell proliferation, and migration; (2) on vascular smooth muscle cells decreasing cell proliferation and migration; and (3) on cardiomyocytes reducing low-density lipoprotein (LDL)-cholesterol level and protecting against insulin resistance, infarct size, and ischemia–reperfusion injury and cardiac hypertrophy. [Powerpoint File]

The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System

The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System

Sara Menazza, Elizabeth Murphy

Genomic estrogen receptor (ER) signaling. A, Direct binding to DNA. Estrogen binding to ERs promotes receptor translocation to the nuclei. ERs bind to the consensus estrogen response element (ERE) in the DNA, mediating its genomic effects. Coactivators and corepressors are recruited to activate or inhibit gene. B, Indirectly binding DNA through other transcription factors. ERs can tether transcription factors (TF) such as API and Sp1 regulating gene expressions. C and D, Ligand-independent binding. ERs can be phosphorylated by kinases signaling (such as p38, extracellular-signal-regulated kinase [ERK], and activation of protein kinase B [Akt]) activated by plasma membrane ERs signaling. Specific serine site phosphorylation of ERs can trigger its binding to DNA, thus activating the transcription via ligand-independent binding or via ERE-binding. MAPK indicates mitogen-activated protein kinase; and PI3K, phosphatidylinositol-3-OH kinase. [Powerpoint File]

The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System

The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System

Sara Menazza, Elizabeth Murphy

Orphan G-protein–coupled receptor (GRP30) activation via endothelium-independent or endothelium-dependent mechanisms. A, Endothelium-independent effect is mediated by a large conductance calcium-activated potassium channel leading to an increase in potassium efflux. This effect results in coronary artery relaxation. BK indicates Ca2+- and voltage-activated K+ channels. B, Endothelium-dependent mechanism. Estrogen binding to GPR30 leads to activation of endothelial nitric oxide (NO) synthase raising the production of NO in coronary endothelial cells to relax these arteries. [Powerpoint File]