Am. J. Respir. Cell Mol. Biol., Volume 26, Number 5, May, 2002 610-616

Estrogen Acutely Activates Prostacyclin Synthesis in Ovine Fetal Pulmonary Artery Endothelium

Todd S. Sherman, Ken L. Chambliss, Linda L. Gibson, Margaret C. Pace, Michael E. Mendelsohn, Sandra L. Pfister, and Philip W. Shaul

Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; and Molecular Cardiology Research Institute, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts

Prostacyclin (PGI₂) is a key mediator of pulmonary vasodilation during perinatal cardiopulmonary transition, at a time when fetal plasma estrogen levels are rising. We have previously shown that estradiol-17 (E₂) rapidly stimulates nitric oxide production by ovine fetal pulmonary artery endothelial cells (PAEC), and that this occurs through nongenomic mechanisms which are calcium- and tyrosine kinase-mitogen-activated protein (MAP) kinase-dependent. In the present study, we determined if E₂ acutely activates PGI₂ production in PAEC. E₂ (10⁸ M for 15 min) caused a 52% increase in PGI₂, the threshold concentration was 10¹⁰ M E₂, the effect occurred within 5 min, and it was not related to changes in cyclooxygenase type 1 (COX-1) or COX-2 abundance. Estrogen receptor (ER)  and ER proteins and mRNAs were found to be constitutively expressed in PAEC, and PGI₂ stimulation with E₂ was fully blocked by both ER antagonism with ICI 182,780, which is not selective for either ER isoform, and the ER-specific antagonist RR-tetrahydrochrysene. The rapid response to E₂ was also inhibited by calcium chelation, whereas genistein- or PD98059-induced inhibition of tyrosine kinase and MAP kinase kinase, respectively, had no effect. Thus, E₂ causes rapid stimulation of PGI₂ synthesis in fetal PAEC, this process is mediated by ER, and it is calcium-dependent and tyrosine kinase-MAP kinase-independent. These mechanisms may play a role in pulmonary vasodilation in the perinatal period.

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