Heme oxygenase (HO) regulates vascular tone and blood pressure through the production of the vasodilator carbon monoxide (CO), derived from the heme degradation pathway. During pregnancy, the maternal circulation undergoes significant adaptations to accommodate for the hemodynamic demands of the developing fetus. Our objective was to investigate the role of HO and its bioactive product, CO, on maternal and fetal hemodynamics during pregnancy. In this study, we hypothesized that CO regulates maternal vascular tone, affecting uteroplacental artery dilation and placental perfusion and subsequently influencing fetal hemodynamic function. Compared with age-matched nonpregnant (control) levels, baseline total body CO excretion (VeCO) rates and blood carboxyhemoglobin (COHb) levels in pregnant mice were significantly elevated as well as HO activity in maternal livers, spleens, and placentas. Placental HO activity was the highest at embryonic ages E12.5 through E15.5. The maternal abdominal aorta (AA) was significantly dilated in pregnant mice compared with nonpregnant controls (0.88 vs 0.68 mm, respectively). To elucidate the function of HO and the production of CO during pregnancy, mice at ≈E12.5 to E14.5 were administered tin mesoporphyrin (SnMP), a potent HO inhibitor, at a dose of 30 μmol/kg, IV. Maternal heart rate and AA diameter, as well as fetal heart rate and umbilical artery blood flow and diameter, were measured using microultrasonography. Two hours post-SnMP administration, VeCO levels were reduced by 20%, and HO activity was significantly inhibited in maternal livers and placentas (80% and 90%, respectively) but only slightly (10%) in the fetal liver. In addition, AA was significantly constricted by 33% (0.88-0.59 mm); this effect was not observed in SnMP-treated nonpregnant mice. Furthermore, maternal heart and respiratory rates were elevated. Umbilical artery blood flow and fetal heart rate increased 44% and 38%, respectively, but umbilical artery diameter did not change. We conclude that during pregnancy, elevated levels of CO are produced by increases in HO activity in the maternal liver and placenta and play an important role in maintaining maternal vascular tone and fetal hemodynamic function.
This work was study was supported in part by the Mary L. Johnson and Christopher Hess Research Funds.
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