PROSTACYCLIN SYNTHESIS IN OVINE PULMONARY-ARTERY IS DEVELOPMENTALLY-REGULATED BY CHANGES IN CYCLOOXYGENASE-1 GENE-EXPRESSION

Prostacyclin (PGI(2)) is a key mediator of pulmonary vasomotor tone during late gestation and in the newborn, and its production in whole lung increases during that period. We investigated the developmental regulation of PGI(2) synthesis in ovine intrapulmonary artery (PA) segments from 110 to 115 d (F1) and 125 to 135 d gestation fetal lambs (F2, term = 144 d) and 1- and 4-wk-old newborn lambs (NB1 and NB2). Basal PGI(2) rose fourfold from Fl to F2, fourfold from F2 to NB1, and twofold from NB1 to NB2. In all age groups 66-72% of PGI(2) was derived from the endothelium. Similar fold increases in PGI(2) were observed with maturation in intact and endothelium-denuded segments. In intact PA from F2, NB1, and NB2, basal PGI(2) synthesis and synthesis maximally stimulated by bradykinin, A23187, or arachidonic acid rose with development in a comparable manner. In contrast, PGI(2) synthesis stimulated by exogenous PGH(2), the product of cyclooxygenase, was similar at all ages. Immunoblot analyses of PA from F2, NB1, and NB2 revealed that there is a sixfold maturational increase in cyclooxygenase-1 protein; the cyclooxygenase-2 isoform was not detectable. Cyclooxygenase-1 mRNA abundance in whole lung also rose with development. Thus, PGI(2) synthesis in ovine PA endothelium and vascular smooth muscle increases markedly during late fetal and early newborn life; the increase is due to a rise in cyclooxygenase activity related to enhanced expression of cyclooxygenase-1. We conclude that there is developmental regulation of PA cyclooxygenase-1 gene expression, and that this may be critical to successful cardiopulmonary transition and function in the newborn.