Abstract

Prostacyclin (PGI₂) is a member of the prostanoid group of eicosanoids that regulate homeostasis, hemostasis, smooth muscle function and inflammation. Prostanoids are derived from arachidonic acid by the sequential actions of phospholipase A₂, cyclooxygenase (COX), and specific prostaglandin (PG) synthases. There are two major COX enzymes, COX1 and COX2, that differ in structure, tissue distribution, subcellular localization, and function. COX1 is largely constitutively expressed, whereas COX2 is induced at sites of inflammation and vascular injury. PGI₂ is produced by endothelial cells and influences many cardiovascular processes. PGI₂ acts mainly on the prostacyclin (IP) receptor, but because of receptor homology, PGI₂ analogs such as iloprost may act on other prostanoid receptors with variable affinities. PGI₂/IP interaction stimulates G protein-coupled increase in cAMP and protein kinase A, resulting in decreased [Ca²⁺]_i, and could also cause inhibition of Rho kinase, leading to vascular smooth muscle relaxation. In addition, PGI₂ intracrine signaling may target nuclear peroxisome proliferator-activated receptors and regulate gene transcription. PGI₂ counteracts the vasoconstrictor and platelet aggregation effects of thromboxane A₂ (TXA₂), and both prostanoids create an important balance in cardiovascular homeostasis. The PGI₂/TXA₂ balance is particularly critical in the regulation of maternal and fetal vascular function during pregnancy and in the newborn. A decrease in PGI₂/TXA₂ ratio in the maternal, fetal, and neonatal circulation may contribute to preeclampsia, intrauterine growth restriction, and persistent pulmonary hypertension of the newborn (PPHN), respectively. On the other hand, increased PGI₂ activity may contribute to patent ductus arteriosus (PDA) and intraventricular hemorrhage in premature newborns. These observations have raised interest in the use of COX inhibitors and PGI₂ analogs in the management of pregnancy-associated and neonatal vascular disorders. The use of aspirin to decrease TXA₂ synthesis has shown little benefit in preeclampsia, whereas indomethacin and ibuprofen are used effectively to close PDA in the premature newborn. PGI₂ analogs have been used effectively in primary pulmonary hypertension in adults and have shown promise in PPHN. Careful examination of PGI₂ metabolism and the complex interplay with other prostanoids will help design specific modulators of the PGI₂-dependent pathways for the management of pregnancy-related and neonatal vascular disorders.