Document Detail

Prolonged ovarian hormone deprivation impairs the protective vascular actions of estrogen receptor alpha agonists.
MedLine Citation:
PMID:  18259018     Owner:  NLM     Status:  MEDLINE    
The vascular consequences of estrogen treatment may be driven by its initiation timing. We tested the hypothesis that the duration of ovarian hormone deprivation before estrogen reintroduction affects the role of estrogen as mediator of endothelial function and vascular relaxation in nondiseased vessels. Rats were ovariectomized and implanted with 17beta-estradiol (E(2)) or oil capsules 1, 4, and 8 months after surgery. After the longest hypoestrogenicity period, acetylcholine-mediated aortic relaxation was attenuated and insensitive to E(2) administration despite endothelial integrity. Whereas no rapid vasorelaxant responses were elicited by an estrogen receptor (ER) beta-selective agonist, responses to E(2) and an ERalpha selective agonist waned postovariectomy at any given time and were restored by E(2) treatment after 1 and 4 months but not 8 months postovariectomy. Accordingly, endothelial ERalpha mRNA and protein expression declined approximately 6-fold after prolonged hypoestrogenicity and was restored by estrogen replacement starting 1 month but not 8 months postovariectomy. Furthermore, the amount of active phosphorylated endothelial NO synthase rose significantly after E(2) replacement after 1 and 4 months but not 8 months postovariectomy. The present findings document that the functional impairment of the ERalpha/endothelial NO synthase signaling network after an extended period of hypoestrogenicity was not restored by E(2) administration, providing experimental support to early initiation of estrogen replacement with preferential ERalpha targeting to improve cardiovascular outcomes.
Christian Pinna; Andrea Cignarella; Paola Sanvito; Valeria Pelosi; Chiara Bolego
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-02-07
Journal Detail:
Title:  Hypertension     Volume:  51     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2008 Apr 
Date Detail:
Created Date:  2008-03-21     Completed Date:  2008-04-16     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1210-7     Citation Subset:  IM    
Department of Pharmacological Sciences, University of Milan, Milan, Italy.
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MeSH Terms
Acetylcholine / pharmacology
Aorta, Thoracic / drug effects*,  physiology
Body Weight
Endothelium, Vascular / drug effects,  physiology
Estradiol / pharmacology*
Estrogen Receptor alpha / agonists*,  genetics,  metabolism
Estrogen Replacement Therapy
Estrogens / pharmacology*
Nitric Oxide Synthase Type II / metabolism
Nitric Oxide Synthase Type III
Nitriles / pharmacology
Organ Size
Propionates / pharmacology
RNA, Messenger / metabolism
Rats, Sprague-Dawley
Time Factors
Uterus / anatomy & histology
Vasodilation / drug effects
Vasodilator Agents / pharmacology
Reg. No./Substance:
0/Estrogen Receptor alpha; 0/Estrogens; 0/Nitriles; 0/Propionates; 0/RNA, Messenger; 0/Vasodilator Agents; 0/diarylpropionitrile; 50-28-2/Estradiol; 51-84-3/Acetylcholine; EC Oxide Synthase Type II; EC Oxide Synthase Type III; EC protein, rat

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