title: Activation of GPER Induces Differentiation and Inhibition of Coronary Artery Smooth Muscle Cell Proliferation.
abstract: Vascular pathology and dysfunction are direct life-threatening outcomes resulting from atherosclerosis or vascular injury, which are primarily attributed to contractile smooth muscle cells (SMCs) dedifferentiation and proliferation by re-entering cell cycle. Increasing evidence suggests potent protective effects of G-protein coupled estrogen receptor 1 (GPER) activation against cardiovascular diseases. However, the mechanism underlying GPER function remains poorly understood, especially if it plays a potential role in modulating coronary artery smooth muscle cells (CASMCs).
  
  
  
  The objective of our study was to understand the functional role of GPER in CASMC proliferation and differentiation in coronary arteries using from humans and swine models. We found that the GPER agonist, G-1, inhibited both human and porcine CASMC proliferation in a concentration- (10(-8) to 10(-5) M) and time-dependent manner. Flow cytometry revealed that treatment with G-1 significantly decreased the proportion of S-phase and G2/M cells in the growing cell population, suggesting that G-1 inhibits cell proliferation by slowing progression of the cell cycle. Further, G-1-induced cell cycle retardation was associated with decreased expression of cyclin B, up-regulation of cyclin D1, and concomitant induction of p21, and partially mediated by suppressed ERK1/2 and Akt pathways. In addition, G-1 induces SMC differentiation evidenced by increased α-smooth muscle actin (α-actin) and smooth muscle protein 22α (SM22α) protein expressions and inhibits CASMC migration induced by growth medium.
  
  
  
  GPER activation inhibits CASMC proliferation by suppressing cell cycle progression via inhibition of ERK1/2 and Akt phosphorylation. GPER may constitute a novel mechanism to suppress intimal migration and/or synthetic phenotype of VSMC.
authors.affiliation: Women's Health Division, Michael E. DeBakey Institute, Texas A&M University, College Station, Texas, United States of America ; College of Life Science, Henan Normal University, Xinxiang, Henan Province, P. R. China.
authors.forename: Fen
authors.initials: F
authors.lastname: Li
authors.forename: Xuan
authors.initials: X
authors.lastname: Yu
authors.forename: Claudia K
authors.initials: CK
authors.lastname: Szynkarski
authors.forename: Cong
authors.initials: C
authors.lastname: Meng
authors.forename: Beiyan
authors.initials: B
authors.lastname: Zhou
authors.forename: Rola
authors.initials: R
authors.lastname: Barhoumi
authors.forename: Richard E
authors.initials: RE
authors.lastname: White
authors.forename: Cristine L
authors.initials: CL
authors.lastname: Heaps
authors.forename: John N
authors.initials: JN
authors.lastname: Stallone
authors.forename: Guichun
authors.initials: G
authors.lastname: Han
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D003517:Cyclopentanes / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology*; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013552:Swine; D015854:Up-Regulation / 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; D011804:Quinolines; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled