Regulation of vascular tone during pregnancy: a novel role for the pregnane X receptor.
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.
Hagedorn
Kathryn A
KA
Perinatal Research Centre, Department of Obstetrics/Gynecology, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Cooke
Christy-Lynn
CL
Falck
John R
JR
Mitchell
Bryan F
BF
Davidge
Sandra T
ST
D043582:5-alpha-Dihydroprogesterone / Q000494:pharmacology; D000222:Adaptation, Physiological; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000502:physiology; D001920:Bradykinin / Q000494:pharmacology; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D005260:Female; D066298:In Vitro Techniques; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009213:Myography; D010105:Oxygenases / Q000037:antagonists & inhibitors; D010656:Phenylephrine / Q000494:pharmacology; D011247:Pregnancy / Q000502:physiology*; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D014666:Vasomotor System / Q000502:physiology*
D000577:Amides; D065607:Cytochrome P-450 Enzyme Inhibitors; C121756:N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D003577:Cytochrome P-450 Enzyme System; D043582:5-alpha-Dihydroprogesterone; D010105:Oxygenases; D000090762:Cytochrome P-450 CYP2J2; D001920:Bradykinin