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


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Abstract

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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