title: The GPER1 agonist G-1 attenuates endothelial cell proliferation by inhibiting DNA synthesis and accumulating cells in the S and G2 phases of the cell cycle.
abstract: G protein-coupled receptor 30 (GPR30) or G protein-coupled estrogen receptor 1 (GPER1) is expressed in the vasculature, but the importance of vascular GPER1 remains to be clarified. Here we investigate effects of the GPER1 agonist G-1 on endothelial cell proliferation using mouse microvascular endothelial bEnd.3 cells. The bEnd.3 cells express mRNA for GPER1. The bEnd.3 cells expressed both ERα and ERβ immunoreactivities. Treatment with G-1 reduced DNA synthesis and cell number with IC(50) values of about 2 μM. GPER1 siRNA prevented G-1-induced attenuation of DNA synthesis. G-1 accumulated cells in S and G2 phases of the cell cycle, suggesting that G-1 blocks transition between G2 and M. G-1 had no effect on DNA synthesis in COS-7 cells only weakly expressing GPER1 mRNA. 17β-Estradiol had no effect on DNA synthesis in physiological concentrations (nM). The ER blocker ICI182780 reduced DNA synthesis with similar potency as G-1. Treatment with the ERK/MAP kinase inhibitor PD98059 had no effect on G-1-induced attenuation of DNA synthesis. G-1- induced antiproliferation was observed not only in bEnd.3 cells but also in human umbilical vein endothelial cells and HMEC-1 endothelial cells. We conclude that the GPER1 agonist G-1 attenuates endothelial cell proliferation via inhibition of DNA synthesis and by accumulation of cells in S and G2.
authors.affiliation: Department of Experimental Medical Science, Lund University, Lund University Hospital, Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Holm
authors.forename: Bo
authors.initials: B
authors.lastname: Baldetorp
authors.forename: Björn
authors.initials: B
authors.lastname: Olde
authors.forename: L M Fredrik
authors.initials: LM
authors.lastname: Leeb-Lundberg
authors.forename: Bengt-Olof
authors.initials: BO
authors.lastname: Nilsson
mesh_terms: D000818:Animals; D019556:COS Cells; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003517:Cyclopentanes / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D051379:Mice; D011804:Quinolines / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000032:analysis; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000032:analysis / Q000502:physiology; D016196:S Phase / Q000187:drug effects*
chemical_list: C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; D003517:Cyclopentanes; C109584:GPER1 protein, human; C532507:GPER1 protein, mouse; D011804:Quinolines; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D004247:DNA