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 (EC50: 2.77 +/- 0.32 mu mol/L versus 5.13 +/- 0.36 mu mol/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 5 beta-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-methylsulphonyl6-( 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.