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Regulation of Maternal and Fetal Hemodynamics by Heme Oxygenase in Mice¹

Departments of Pediatrics³ and Obstetrics and Gynecology,⁴ Stanford University School of Medicine, Stanford, California 94305

ABSTRACT

Heme oxygenase (HMOX) regulates vascular tone and blood pressure through the production of carbon monoxide (CO), a vasodilator derived from the heme degradation pathway. During pregnancy, the maternal circulation undergoes significant adaptations to accommodate the hemodynamic demands of the developing fetus. Our objective was to investigate the role of HMOX on maternal and fetal hemodynamics during pregnancy in a mouse model. We measured and compared maternal tissue and placental HMOX activity and endogenous CO production, represented by excreted CO and carboxyhemoglobin levels, during pregnancy (Embryonic Days 12.5–15.5) to nonpregnant controls. Micro-ultrasound was used to monitor maternal abdominal aorta diameters as well as blood flow velocities and diameters of fetal umbilical arteries. Tin mesoporphyrin, a potent HMOX inhibitor, was used to inhibit HMOX activity. Changes in maternal vascular tone were monitored by tail cuff blood pressure measurements. Effects of HMOX inhibition on placental structures were assessed by histology. We showed that maternal tissue and placental HMOX activity and CO production were significantly elevated during pregnancy. When HMOX in the placenta was inhibited, maternal and fetal hemodynamics underwent significant changes, with maternal blood pressures increasing. We concluded that increases in maternal tissue and placental HMOX activity contribute to the regulation of peripheral vascular resistance and therefore are important for the maintenance of normal maternal vascular tone and fetal hemodynamic functions during pregnancy.

carbon monoxide, heme oxygenase, hemodynamic function, hemodynamics, placenta, pregnancy

¹Supported by National Institutes of Health grant HL58013, the Hess Research Fund, and the Mary L. Johnson Research Fund.

Correspondence: ²Hui Zhao, Department of Pediatrics, Division of Neonatology & Developmental Medicine, Stanford University School of Medicine, Grant Building S230, 300 Pasteur Drive, Stanford, CA 94305-5208. FAX: 650 725 7724; e-mail: huizhao2{at}stanford.edu