Estrogen signals to the preservation of endothelial cell form and function.
Estrogen is important for the primary prevention of vascular disease in young women, but the mechanisms of protection at the vascular cell are still largely unknown. Although traditionally thought of as a nuclear transcription factor, the estrogen receptor has also been identified in the cell plasma membrane to signal but serve largely undefined roles. Here we show that estradiol (E2) rapidly activates p38beta mitogen-activated protein kinase in endothelial cells (EC), which activates the mitogen-activated protein kinase-activated protein kinase-2 and the phosphorylation of heat shock protein 27. The sex steroid preserves the EC stress fiber formation and actin and membrane integrity in the setting of metabolic insult. E2 also prevents hypoxia-induced apoptosis and induces both the migration of EC and the formation of primitive capillary tubes. These effects are reversed by the inhibition of p38beta, by the expression of a dominant-negative mitogen-activated protein kinase-activated protein kinase-2 protein, or by the expression of a phosphorylation site mutant heat shock protein 27. E2 signaling from the membrane helps preserve the EC structure and function, defining potentially important vascular-protective effects of this sex steroid.
Razandi
M
M
Division of Endocrinology, Veterans Affairs Medical Center, Long Beach, California 90822, USA.
Pedram
A
A
Levin
E R
ER
D000818:Animals; D001011:Aorta; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D015687:Cell Hypoxia; D002465:Cell Movement / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008833:Microcirculation; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D004958:Estradiol; D004965:Estrogen Antagonists; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D010710:Phosphates; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D011994:Recombinant Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C057725:HSPB1 protein, human; C093642:SB 203580