Production Of PGI2 By Cultured Endothelial Cells And Smooth Muscle Cells

Abstract

Prostacyclin (PGI2) is the main product of the cyclooxygenase pathway in endothelial cells and is a short-lived vasodilator and inhibitor of platelet aggregation. Cultured endothelial cells (EC) make PGI2 from exogenous arachidonic acid (AA) and the unstable endoperoxide PGH2. EC have also been shown to make PGI2 from endogenous AA when stimulated by the calcium ionophore A23187, thrombin, histamine, bradykinin, trypsin, platelet derived growth factor, and uremic plasma. PGI2 synthesis in EC is blocked by aspirin, indomethacin, or 15-HPAA. PGI2 synthesis is partially self-controlled and self-limiting at least in vitro since PGI2 elevates EC cAMP levels and elevated cAMP levels decrease EC PGI2 production. While the proteolytic site of thrombin (and trypsin) is involved in the stimulation of PGI2 production, high affinity binding of thrombin to endothelial cells appears not to be necessary. Alteration of the fatty acid composition of EC by manipulation of the culture media can decrease PGI2 production in response to thrombin or A23187 by 60-751. Cultured aortic smooth muscle cells (SMC) also synthesize PGI2 but at significantly lower levels than EC. SMC PGI2 production is stimulated by PDGF and in some SMC lines by thrombin. SMC grown from atherosclerotic rabbit aortas produce considerably less PGI2 from exogenous AA than do SMC from noimal aortas. Future investigations into this area will further clarify normal biochemical and physiologic pathways and perhaps suggest means by which PGI2 production in EC and SMC may be modulated in order to treat human disease.