title: G protein-coupled estrogen receptor inhibits vascular prostanoid production and activity.
abstract: Complications of atherosclerotic vascular disease, such as myocardial infarction and stroke, are the most common causes of death in postmenopausal women. Endogenous estrogens inhibit vascular inflammation-driven atherogenesis, a process that involves cyclooxygenase (COX)-derived vasoconstrictor prostanoids such as thromboxane A2. Here, we studied whether the G protein-coupled estrogen receptor (GPER) mediates estrogen-dependent inhibitory effects on prostanoid production and activity under pro-inflammatory conditions. Effects of estrogen on production of thromboxane A(2) were determined in human endothelial cells stimulated by the pro-inflammatory cytokine tumour necrosis factor alpha (TNF-α). Moreover, Gper-deficient (Gper(-/-)) and WT mice were fed a pro-inflammatory diet and underwent ovariectomy or sham surgery to unmask the role of endogenous estrogens. Thereafter, contractions to acetylcholine-stimulated endothelial vasoconstrictor prostanoids and the thromboxane-prostanoid receptor agonist U46619 were recorded in isolated carotid arteries. In endothelial cells, TNF-α-stimulated thromboxane A2 production was inhibited by estrogen, an effect blocked by the GPER-selective antagonist G36. In ovary-intact mice, deletion of Gper increased prostanoid-dependent contractions by twofold. Ovariectomy also augmented prostanoid-dependent contractions by twofold in WT mice but had no additional effect in Gper(-/-) mice. These contractions were blocked by the COX inhibitor meclofenamate and unaffected by the nitric oxide synthase inhibitor l-N(G)-nitroarginine methyl ester. Vasoconstrictor responses to U46619 did not differ between groups, indicating intact signaling downstream of thromboxane-prostanoid receptor activation. In summary, under pro-inflammatory conditions, estrogen inhibits vasoconstrictor prostanoid production in endothelial cells and activity in intact arteries through GPER. Selective activation of GPER may therefore be considered as a novel strategy to treat increased prostanoid-dependent vasomotor tone or vascular disease in postmenopausal women.
authors: Department of Internal MedicineUniversity of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, New Mexico 87131, USADepartment of CardiologyCantonal Hospital, Tellstrasse, 5001 Aarau, SwitzerlandMolecular Internal MedicineUniversity of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland Department of Internal MedicineUniversity of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, New Mexico 87131, USADepartment of CardiologyCantonal Hospital, Tellstrasse, 5001 Aarau, SwitzerlandMolecular Internal MedicineUniversity of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland matthias.meyer@ksa.ch eprossnitz@salud.unm.edu.
authors: Matthias R
authors: MR
authors: Meyer
authors: Department of Internal MedicineUniversity of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, New Mexico 87131, USADepartment of CardiologyCantonal Hospital, Tellstrasse, 5001 Aarau, SwitzerlandMolecular Internal MedicineUniversity of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors: Natalie C
authors: NC
authors: Fredette
authors: Department of Internal MedicineUniversity of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, New Mexico 87131, USADepartment of CardiologyCantonal Hospital, Tellstrasse, 5001 Aarau, SwitzerlandMolecular Internal MedicineUniversity of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors: Matthias
authors: M
authors: Barton
authors: Department of Internal MedicineUniversity of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, New Mexico 87131, USADepartment of CardiologyCantonal Hospital, Tellstrasse, 5001 Aarau, SwitzerlandMolecular Internal MedicineUniversity of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland matthias.meyer@ksa.ch eprossnitz@salud.unm.edu.
authors: Eric R
authors: ER
authors: Prossnitz
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001167:Arteritis / Q000276:immunology / Q000378:metabolism; D052117:Benzodioxoles / Q000494:pharmacology; D017536:Carotid Artery, Common / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002461:Cell Line, Transformed; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010052:Ovariectomy; D011804:Quinolines / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D052117:Benzodioxoles; D004967:Estrogens; C000603178:G36 compound; C109584:GPER1 protein, human; C532507:GPER1 protein, mouse; D011804:Quinolines; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
keywords: GPER; GPR30; acetylcholine; atherosclerosis; cyclooxygenase; estrogen; inflammation; menopause; ovariectomy; vasoconstriction