title: Extent of Vascular Remodeling Is Dependent on the Balance Between Estrogen Receptor α and G-Protein-Coupled Estrogen Receptor.
abstract: Estrogens are important regulators of cardiovascular function. Some of estrogen's cardiovascular effects are mediated by a G-protein-coupled receptor mechanism, namely, G-protein-coupled estrogen receptor (GPER). Estradiol-mediated regulation of vascular cell programmed cell death reflects the balance of the opposing actions of GPER versus estrogen receptor α (ERα). However, the significance of these opposing actions on the regulation of vascular smooth muscle cell proliferation or migration in vitro is unclear, and the significance in vivo is unknown. To determine the effects of GPER activation in vitro, we studied rat aortic vascular smooth muscle cells maintained in primary culture. GPER was reintroduced using adenoviral gene transfer. Both estradiol and G1, a GPER agonist, inhibited both proliferation and cell migration effects that were blocked by the GPER antagonist, G15. To determine the importance of the GPER-ERα balance in regulating vascular remodeling in a rat model of carotid ligation, we studied the effects of upregulation of GPER expression versus downregulation of ERα. Reintroduction of GPER significantly attenuated the extent of medial hypertrophy and attenuated the extent of CD45 labeling. Downregulation of ERα expression comparably attenuated the extent of medial hypertrophy and inflammation after carotid ligation. These studies demonstrate that the balance between GPER and ERα regulates vascular remodeling. Receptor-specific modulation of estrogen's effects may be an important new approach in modifying vascular remodeling in both acute settings like vascular injury and perhaps in longer term regulation like in hypertension.
authors.affiliation: From the Department of Medicine (R.G., J.C., J.G.P., R.D.F.) and Department of Physiology and Pharmacology (R.G., J.G.P.), Robarts Research Institute, Western University, London, Ontario, Canada; Weill-Cornell School of Medicine, New York, New York (Y.H.); and Discipline of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada (Q.D., R.D.F.).
authors.forename: Robert
authors.initials: R
authors.lastname: Gros
authors.affiliation: From the Department of Medicine (R.G., J.C., J.G.P., R.D.F.) and Department of Physiology and Pharmacology (R.G., J.G.P.), Robarts Research Institute, Western University, London, Ontario, Canada; Weill-Cornell School of Medicine, New York, New York (Y.H.); and Discipline of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada (Q.D., R.D.F.).
authors.forename: Yasin
authors.initials: Y
authors.lastname: Hussain
authors.affiliation: From the Department of Medicine (R.G., J.C., J.G.P., R.D.F.) and Department of Physiology and Pharmacology (R.G., J.G.P.), Robarts Research Institute, Western University, London, Ontario, Canada; Weill-Cornell School of Medicine, New York, New York (Y.H.); and Discipline of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada (Q.D., R.D.F.).
authors.forename: Jozef
authors.initials: J
authors.lastname: Chorazyczewski
authors.affiliation: From the Department of Medicine (R.G., J.C., J.G.P., R.D.F.) and Department of Physiology and Pharmacology (R.G., J.G.P.), Robarts Research Institute, Western University, London, Ontario, Canada; Weill-Cornell School of Medicine, New York, New York (Y.H.); and Discipline of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada (Q.D., R.D.F.).
authors.forename: J Geoffrey
authors.initials: JG
authors.lastname: Pickering
authors.affiliation: From the Department of Medicine (R.G., J.C., J.G.P., R.D.F.) and Department of Physiology and Pharmacology (R.G., J.G.P.), Robarts Research Institute, Western University, London, Ontario, Canada; Weill-Cornell School of Medicine, New York, New York (Y.H.); and Discipline of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada (Q.D., R.D.F.).
authors.forename: Qingming
authors.initials: Q
authors.lastname: Ding
authors.affiliation: From the Department of Medicine (R.G., J.C., J.G.P., R.D.F.) and Department of Physiology and Pharmacology (R.G., J.G.P.), Robarts Research Institute, Western University, London, Ontario, Canada; Weill-Cornell School of Medicine, New York, New York (Y.H.); and Discipline of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada (Q.D., R.D.F.). ross.feldman@med.mun.ca.
authors.forename: Ross D
authors.initials: RD
authors.lastname: Feldman
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002339:Carotid Arteries / Q000601:surgery; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D008026:Ligation / Q000379:methods; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000254:growth & development*; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D015854:Up-Regulation; D066253:Vascular Remodeling / Q000235:genetics*
chemical_list: D047628:Estrogen Receptor alpha; C520305:Gper1 protein, rat; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled
keywords: apoptosis; estradiol; estrogen; inflammation