Am. J. Respir. Cell Mol. Biol., Volume 20, Number 1, January, 1999 113-121

Developmental Changes in Prostacyclin Synthesis Are Conserved in Cultured Pulmonary Endothelium and Vascular Smooth Muscle

Philip W. Shaul, Margaret C. Pace, Zhong Chen, and Timothy S. Brannon

Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas

Prostacyclin (PGI₂) is a key mediator of pulmonary vascular and parenchymal function during late fetal and early postnatal life, and its synthesis in intrapulmonary arteries increases markedly during that period. The rate-limiting enzyme in PGI₂ synthesis in the developing lung is cyclooxygenase (COX). To understand better the mechanisms underlying the developmental increase in PGI₂ synthesis, we evaluated PGI₂ production in early-passage, cultured pulmonary artery endothelial cells (PAEC) and pulmonary vascular smooth-muscle cells (VSM) from fetal and newborn lambs. In arterial segments, PGI₂ synthesis was sevenfold greater in intact arteries from newborn than from fetal lambs, and it was 12-fold greater in endothelium-denuded newborn than in fetal arteries, indicating that the developmental increase occurs in both the endothelium and medial layer. Similarly, basal PGI₂ production was three-fold greater in newborn than in fetal PAEC, and 2.5-fold greater in newborn than in fetal pulmonary VSM cells. Calcium ionophore (A23187)-stimulated and arachidonic acid-stimulated PGI₂ synthesis were also greater in newborn than in fetal PAEC and VSM, revealing a developmental upregulation in COX enzymatic activity in both cell types. Immunoblot analysis showed that this is due to greater COX-1 protein expression in newborn than in fetal vascular cells; COX-2 protein expression was not detected. In addition, COX-1 messenger RNA (mRNA) abundance was greater in newborn than in fetal PAEC, and this was not due to a difference in COX-1 mRNA stability. Thus, the developmental upregulation of PGI₂ synthesis is conserved in early-passage PAEC and pulmonary VSM, and is related to a maturational increase in COX-1 gene expression. Further studies with the cultured cell model will enable determination of the factors that directly regulate COX-1 expression in the developing pulmonary vasculature.

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