Developmental changes in prostacyclin synthesis are conserved in cultured pulmonary endothelium and vascular smooth muscle

Prostacyclin (PGI,) 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-lim iting enzyme in PGI, synthesis in the developing lung is cyclooxygenase (CO X). To understand better the mechanisms underlying the developmental increa se in PGI, synthesis, we evaluated PGI, production in early-passage, cultur ed pulmonary artery endothelial cells (PAEC) and pulmonary vascular smooth- muscle cells (VSM) from fetal and newborn lambs. In arterial segments, PGI( 2) synthesis was sevenfold greater in intact arteries from newborn than fro m fetal lambs, and it was 12-fold greater in endothelium-denuded newborn th an in fetal arteries, indicating that the developmental increase occurs in both the endothelium and medial layer. Similarly, basal PGI, 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)-stimu lated and arachidonic acid-stimulated PGI(2) 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 t hat this is due to greater COX-1 protein expression in newborn than in feta l vascular cells; COX-2 protein expression was not detected. In addition, C OX-1 messenger RNA (mRNA) abundance was greater in newborn than in fetal PA EC, 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.