title: Vasodilatory effects of the selective GPER agonist G-1 is maximal in arteries of postmenopausal women.
abstract: G-protein-coupled estrogen receptors (GPERs) have been proposed to mediate estrogen-mediated vasodilation. The presence of GPER-dependent vasodilation in human resistance-sized arteries (HRAs) or its signal transduction pathways have not been investigated. HRAs in subcutaneous fat tissues (biopsies from postmenopausal women (PMW), age-matched men (M) and pregnant women (PGW)) were mounted for in vitro isometric force recording. Vasodilation induced by G-1 (selective GPER-agonist, 3 μM) from HRAs pre-contracted with norepinephrine amounted to 40±5% in PMW, significantly larger than those obtained from M (20±5%) or PGW (20±5%). L-NAME (nitric oxide (NO) synthase inhibitor) abolished these relaxations in PGW, attenuated them in PMW and had no effect in M. Immunohistochemical analysis confirmed the presence of GPER in both smooth muscle and endothelial cells of HRA with maximum expression in PGW. In cultured human umbilical vein endothelial cells (HUVECs), G-1 increased NO-synthesis concentration-dependently through higher expressions of endothelial NO-synthase (eNOS) and through enhanced phosphorylation of eNOS on Ser(1177). In conclusion, GPER vasodilates human resistance arteries through various activating mechanisms of the eNOS-signaling pathway.
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. Electronic address: samsul.arefin@ki.se.
authors.forename: Samsul
authors.initials: S
authors.lastname: Arefin
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Simoncini
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Wieland
authors.affiliation: Division of Surgery, Gastrocentrum Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Folke
authors.initials: F
authors.lastname: Hammarqvist
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Spina
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Goglia
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Center for Gender Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address: karolina.kublickiene@ki.se.
authors.forename: Karolina
authors.initials: K
authors.lastname: Kublickiene
mesh_terms: D000368:Aged; D001158:Arteries / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009638:Norepinephrine; D010766:Phosphorylation; D017698:Postmenopause / Q000378:metabolism*; D011247:Pregnancy / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D015398:Signal Transduction; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D004967:Estrogens; C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D020845:Selective Estrogen Receptor Modulators; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine
keywords: Cardiovascular diseases; Endothelium; GPER; Smooth muscle; Vascular smooth muscle cells; Vasodilation