The Influence of Isoprostanes on Angiogenesis In Vitro

Isoprostanes are generated via free radical-induced lipid peroxidation of arachidonic acid. They are by-products of the formation of prostagrandins from arachidonic acid, catalysed by the prostaglandin H2-synthase. Isoprostanes differ from their enzymatic analogues to their regio- and stereochemistry. Theoretically each isoprostane family consist of four regioisomers and 64 stereoisomers. Among the isoprostanes, 8-iso-Prostaglandin F2alpha and 8-iso-Prostaglandin E2 are prominent due to their thromboxane A2 -mediated biological activity. The present work reported that the isoprostanes 8-iso-Prostaglandin F2alpha, 8-iso-Prostaglandin E2, and 8-iso-Prostaglandin A2 inhibit the VEGF-induced migration and tube formation of endothelial cellss in vitro, which represent essential steps in angiogenesis. Simultaneous addition of 8-iso-Prostaglandin F2alpha, 8-iso-Prostaglandin E2, and 8-iso-Prostaglandin A2 exert a synergistic inhibitory effect on endothelial cell migration and tube formation. These data have important implications in settings where release of VEGF and increased isoprostanes formation coincide, such as myocardial ischemia in patients suffering from coronary heart disease. Concerning this matter isoprostanes might counteract VEGF-induced neovascularization processes and therefore prevent improved oxygen supply to the hypoxic tissue. Experiments in the absence of VEGF showed that 8-iso-Prostaglandin F2alpha affects basal migration and tube formation of endothelial cells in a biphasic fashion, with a stimulating effect at low concentrations and an inhibitory effect at high concentrations. However, the physiological relevance of these findings remains unclear due to the fact that VEGF is abundant presence in vivo. It could be identified that isoprostanes exert their inhibiting effects on VEGF-induced endothelial cell migration and tube formation via activation of the thromboxane A2-receptor. Further investigations indicate that thromboxane A2-receptor-induced Rho kinase overactivation might play a key role in isoprostanes-mediated anti-angiogenic effects. This data contribute to an improved understanding of the molecular mechanisms of isoprostanes-mediated anti-angiogenic effects. Thromboxane A2-receptor antagonists or Rho kinase inhibitors may represent new therapeutic strategies to combat capillary rarefication which has been observed in pathophysiological settings, such as oxidative stress-associated coronary heart disease. Isoprostane werden durch