Document Detail


Regulation of vascular tone during pregnancy: a novel role for the pregnane X receptor.
MedLine Citation:
PMID:  17159084     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
During pregnancy, maternal vascular function is altered through mechanisms that remain unclear. Progesterone synthesis and metabolism are also increased. Progesterone metabolites are potent endogenous ligands for the pregnane X receptor (PXR), a nuclear receptor that induces the expression of hepatic cytochrome P450 enzymes. Cytochrome P450 enzymes located in the vasculature can metabolize arachidonic acid to produce epoxyeicosatrienoic acids, known vasodilators. We hypothesized that PXR is present in vascular tissue and contributes to vascular adaptations to pregnancy. PXR mRNA was detected in mouse mesenteric arteries by quantitative RT-PCR. Constrictor and relaxation responses in wildtype (PXR(+/+)) and PXR-deficient (PXR(-/-)) mice were compared by wire myography. Relative to nonpregnant controls, arteries from pregnant PXR(+/+) mice had reduced sensitivity to phenylephrine-induced constriction (EC(50): 2.77+/-0.32 mumol/L versus 5.13+/-0.36 mumol/L; P=0.009) and enhanced maximal vasorelaxation to bradykinin (26+/-3% versus 44+/-16%; P=0.013). However, these pregnancy adaptations were absent in PXR(-/-) mice. We also hypothesized that PXR is activated by progesterone metabolites. Treatment of PXR(+/+) and PXR(-/-) nonpregnant mice with 5beta-dihydroprogesterone for 7 days enhanced endothelium-dependent relaxation in only the PXR(+/+) mice, similarly to that seen in pregnancy. In treated mice, inhibition of cytochrome P450 epoxygenase activity with N-methylsulphonyl-6-(2-propargyloxyphenyl)hexanamide attenuated vasorelaxation in arteries from PXR(+/+) but not PXR(-/-) mice. We conclude that PXR contributes to the development of vascular adaptations to pregnancy, likely in response to activation by progesterone metabolites, and that PXR-dependent increases in vasorelaxation may be because of activation of cytochrome P450 epoxygenases.
Authors:
Kathryn A Hagedorn; Christy-Lynn Cooke; John R Falck; Bryan F Mitchell; Sandra T Davidge
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-12-11
Journal Detail:
Title:  Hypertension     Volume:  49     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-01-19     Completed Date:  2007-02-02     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  328-33     Citation Subset:  IM    
Affiliation:
Perinatal Research Centre, Department of Obstetrics/Gynecology, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
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MeSH Terms
Descriptor/Qualifier:
5-alpha-Dihydroprogesterone / pharmacology
Adaptation, Physiological
Amides / pharmacology
Animals
Blood Vessels / metabolism,  physiology
Bradykinin / pharmacology
Cytochrome P-450 Enzyme System / antagonists & inhibitors
Female
Mesenteric Arteries / drug effects,  metabolism,  physiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Myography
Oxygenases / antagonists & inhibitors
Phenylephrine / pharmacology
Pregnancy / physiology*
RNA, Messenger / metabolism
Receptors, Steroid / genetics,  physiology*
Reverse Transcriptase Polymerase Chain Reaction
Vasoconstriction / drug effects
Vasoconstrictor Agents / pharmacology
Vasodilation / drug effects
Vasodilator Agents / pharmacology
Vasomotor System / physiology*
Grant Support
ID/Acronym/Agency:
GM31278/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Amides; 0/N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; 0/RNA, Messenger; 0/Receptors, Steroid; 0/Vasoconstrictor Agents; 0/Vasodilator Agents; 0/pregnane X receptor; 566-65-4/5-alpha-Dihydroprogesterone; 58-82-2/Bradykinin; 59-42-7/Phenylephrine; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.13.-/Oxygenases; EC 1.14.14.1/arachidonate epoxygenase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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