Document Detail


17β-Estradiol attenuates hypoxic pulmonary hypertension via estrogen receptor-mediated effects.
MedLine Citation:
PMID:  22383500     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RATIONALE: 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.
OBJECTIVES: 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.
MEASUREMENTS AND MAIN 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:
Tim Lahm; Marjorie Albrecht; Amanda J Fisher; Mona Selej; Neel G Patel; Jordan A Brown; Matthew J Justice; M Beth Brown; Mary Van Demark; Kevin M Trulock; Dino Dieudonne; Jagadeshwar G Reddy; Robert G Presson; Irina Petrache
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-03-01
Journal Detail:
Title:  American journal of respiratory and critical care medicine     Volume:  185     ISSN:  1535-4970     ISO Abbreviation:  Am. J. Respir. Crit. Care Med.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-02     Completed Date:  2012-06-22     Revised Date:  2014-10-15    
Medline Journal Info:
Nlm Unique ID:  9421642     Medline TA:  Am J Respir Crit Care Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  965-80     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Airway Remodeling / drug effects,  physiology
Animals
Anoxia / complications*,  drug therapy,  physiopathology
Blood Pressure / drug effects,  physiology
Cardiac Output / drug effects,  physiology
Cyclin-Dependent Kinase Inhibitor p27 / drug effects,  physiology
Estradiol / analogs & derivatives,  pharmacology*,  therapeutic use
Estradiol Antagonists / pharmacology
Hypertension, Pulmonary / drug therapy*,  etiology,  physiopathology
Lung / blood supply,  physiopathology
Male
Neovascularization, Pathologic / drug therapy,  physiopathology
Rats
Rats, Sprague-Dawley
Receptors, Estrogen / drug effects*,  physiology
Ventricular Remodeling / drug effects,  physiology
Grant Support
ID/Acronym/Agency:
R01 HL105772/HL/NHLBI NIH HHS; T32HL091816-03/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cdkn1b protein, rat; 0/Estradiol Antagonists; 0/Receptors, Estrogen; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 22X328QOC4/fulvestrant; 4TI98Z838E/Estradiol
Comments/Corrections
Comment In:
Autophagy. 2012 Jul 1;8(7):1146-7   [PMID:  22627195 ]

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