title: 17β-Estradiol attenuates hypoxic pulmonary hypertension via estrogen receptor-mediated effects.
abstract: BACKGROUND
  17β-Estradiol (E2) attenuates hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension (HPH) through an unknown mechanism that may involve estrogen receptors (ER) or E2 conversion to catecholestradiols and methoxyestradiols with previously unrecognized effects on cardiopulmonary vascular remodeling.
  
  
  OBJECTIVE
  To determine the mechanism by which E2 exerts protective effects in HPH.
  
  
  METHODS
  Male rats were exposed to hypobaric hypoxia while treated with E2 (75 μg/kg/d) or vehicle. Subgroups were cotreated with pharmacologic ER-antagonist or with inhibitors of E2-metabolite conversion. Complementary studies were performed in rats cotreated with selective ERα- or ERβ-antagonist. Hemodynamic and pulmonary artery (PA) and right ventricular (RV) remodeling parameters, including cell proliferation, cell cycle, and autophagy, were measured in vivo and in cultured primary rat PA endothelial cells.
  
  
  RESULTS
  E2 significantly attenuated HPH endpoints. Hypoxia increased ERβ but not ERα lung vascular expression. Co-treatment with nonselective ER inhibitor or ERα-specific antagonist rendered hypoxic animals resistant to the beneficial effects of E2 on cardiopulmonary hemodynamics, whereas ERα- and ERβ-specific antagonists opposed the remodeling effects of E2. In contrast, inhibition of E2-metabolite conversion did not abolish E2 protection. E2-treated hypoxic animals exhibited reduced ERK1/2 activation and increased expression of cell-cycle inhibitor p27(Kip1) in lungs and RV, with up-regulation of lung autophagy. E2-induced signaling was recapitulated in hypoxic but not normoxic endothelial cells, and was associated with decreased vascular endothelial growth factor secretion and cell proliferation.
  
  
  CONCLUSIONS
  E2 attenuates hemodynamic and remodeling parameters in HPH in an ER-dependent manner, through direct antiproliferative mechanisms on vascular cells, which may provide novel nonhormonal therapeutic targets for HPH.
authors.affiliation: Division of Pulmonary, Allergy, Critical Care and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. tlahm@iupui.edu
authors.forename: Tim
authors.initials: T
authors.lastname: Lahm
authors.forename: Marjorie
authors.initials: M
authors.lastname: Albrecht
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Fisher
authors.forename: Mona
authors.initials: M
authors.lastname: Selej
authors.forename: Neel G
authors.initials: NG
authors.lastname: Patel
authors.forename: Jordan A
authors.initials: JA
authors.lastname: Brown
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Justice
authors.forename: M Beth
authors.initials: MB
authors.lastname: Brown
authors.forename: Mary
authors.initials: M
authors.lastname: Van Demark
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Trulock
authors.forename: Dino
authors.initials: D
authors.lastname: Dieudonne
authors.forename: Jagadeshwar G
authors.initials: JG
authors.lastname: Reddy
authors.forename: Robert G
authors.initials: RG
authors.lastname: Presson
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002302:Cardiac Output / Q000187:drug effects / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D004965:Estrogen Antagonists / Q000494:pharmacology; D000077267:Fulvestrant; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D008168:Lung / Q000098:blood supply / Q000503:physiopathology; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology
chemical_list: C493962:Cdkn1b protein, rat; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077267:Fulvestrant; D004958:Estradiol