Roles of thromboxane A2 and prostacyclin in the development of atherosclerosis in apoE-deficient mice

Production of thromboxane (TX) A(2) and PGI(2)/prostacyclin (PGI(2)) is increased in patients with atherosclerosis. However, their roles in atherogenesis have not been critically defined. To examine this issue, we cross-bred atherosclerosis-prone apoE-deficient mice with mice deficient in either the TXA receptor (TP) or the PGI receptor (IP). Although they showed levels of serum cholesterol and triglyceride similar to those of apoE-deficient mice, apoE(-/-)TP(-/-) mice exhibited a significant delay in atherogenesis, and apoE(-/-)IP(-/-) mice exhibited a significant acceleration in atherogenesis compared with mice deficient in apoE alone. The plaques in apoE(-/-)IP(-/-) mice showed partial endothelial disruption and exhibited enhanced expression of ICAM-1 and decreased expression of platelet endothelial cell adhesion molecule 1 (PECAM-1) in the overlying endothelial cells compared with those of apoE(-/-)TP(-/-) mice. Platelet activation with thrombin ex vivo revealed higher and lower sensitivity for surface P-selectin expression in platelets of apoE(-/-)IP(-/-) and apoE(-/-)TP(-/-) mice, respectively, than in those of apoE(-/-) mice. Intravital microscopy of the common carotid artery revealed a significantly greater number of leukocytes rolling on the vessel walls in apoE(-/-)IP(-/-) mice than in either apoE(-/-)TP(-/-) or apoE(-/-) mice. We conclude that TXA(2) promotes and PGI(2) prevents the initiation and progression of atherogenesis through control of platelet activation and leukocyte-endothelial cell interaction.