title: GPER activation ameliorates aortic remodeling induced by salt-sensitive hypertension.
abstract: The mRen2 female rat is an estrogen- and salt-sensitive model of hypertension that reflects the higher pressure and salt sensitivity associated with menopause. We previously showed that the G protein-coupled estrogen receptor (GPER) mediates estrogenic effects in this model. The current study hypothesized that GPER protects against vascular injury during salt loading. Intact mRen2 female rats were fed a normal (NS; 0.5% Na(+)) or high-salt diet (HS; 4% Na(+)) for 10 wk, which significantly increased systolic blood pressure (149 ± 5 vs. 224 ± 8 mmHg;P< 0.001). Treatment with the selective GPER agonist G-1 for 2 wk did not alter salt-sensitive hypertension (216 ± 4 mmHg;P> 0.05) or ex vivo vascular responses to angiotensin II or phenylephrine (P> 0.05). However, G-1 significantly attenuated salt-induced aortic remodeling assessed by media-to-lumen ratio (NS: 0.43; HS+veh: 0.89; HS+G-1: 0.61;P< 0.05). Aortic thickening was not accompanied by changes in collagen, elastin, or medial proliferation. However, HS induced increases in medial layer glycosaminoglycans (0.07 vs. 0.42 mm(2);P< 0.001) and lipid peroxidation (0.11 vs. 0.51 mm(2);P< 0.01), both of which were reduced by G-1 (0.20 mm(2)and 0.23 mm(2); both P< 0.05). We conclude that GPER's beneficial actions in the aorta of salt-loaded mRen2 females occur independently of changes in blood pressure and vasoreactivity. GPER-induced attenuation of aortic remodeling was associated with a reduction in oxidative stress and decreased accumulation of glycosaminoglycans. Endogenous activation of GPER may protect females from salt- and pressure-induced vascular damage.
authors.affiliation: Department of Pharmacology, Tulane University, New Orleans, Louisiana;
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Tulane University, New Orleans, Louisiana;
authors.forename: Shreya
authors.initials: S
authors.lastname: Kashyap
authors.affiliation: Department of Pharmacology, Tulane University, New Orleans, Louisiana;
authors.forename: Brennah
authors.initials: B
authors.lastname: Murphy
authors.affiliation: Department of Pharmacology, Tulane University, New Orleans, Louisiana;
authors.forename: Dillion D
authors.initials: DD
authors.lastname: Hutson
authors.affiliation: Department of Pharmacology, Tulane University, New Orleans, Louisiana;
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Budish
authors.affiliation: Department of Pharmacology, Tulane University, New Orleans, Louisiana;
authors.forename: Emma H
authors.initials: EH
authors.lastname: Trimmer
authors.affiliation: Department of Pharmacology, Tulane University, New Orleans, Louisiana;
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Zimmerman
authors.affiliation: Center for Cardiovascular and Pulmonary Research, Nationwide Children's Hospital, Columbus, Ohio;
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Trask
authors.affiliation: Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana; and.
authors.forename: Kristin S
authors.initials: KS
authors.lastname: Miller
authors.affiliation: Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Chappell
authors.affiliation: Department of Pharmacology, Tulane University, New Orleans, Louisiana; lindsey@tulane.edu.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Lindsey
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D020296:Animals, Congenic; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006025:Glycosaminoglycans / Q000378:metabolism; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D055647:Rats, Transgenic; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism; D017673:Sodium Chloride, Dietary; D013997:Time Factors; D066253:Vascular Remodeling / 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; D006025:Glycosaminoglycans; C520305:Gper1 protein, rat; D011804:Quinolines; D043562:Receptors, G-Protein-Coupled; D017673:Sodium Chloride, Dietary; D000804:Angiotensin II; D010656:Phenylephrine; D012083:Renin
keywords: estrogen; glycosaminoglycans; oxidative stress; salt-sensitive hypertension; vascular remodeling