Effect of 15-lipoxygenase metabolites on angiogenesis: 15(S)-HPETE is angiostatic and 15(S)-HETE is angiogenic

Abstract

15(S)-Hydroxyeicosatetraenoic acid [15(S)-HETE] and 15(S)-hydroperoxyeicosatetraenoic acid [15(S)-HPETE] are the products of arachidonic acid formed in the 15-lipoxygenase pathway. They have opposing effects on the inflammatory process. The present study was designed to examine the role of these metabolites on angiogenesis, which is critically associated with inflammatory conditions. Chick chorio-allantoic membrane (CAM), rat aortic rings and human umbilical vein endothelial cells (HUVECs) in culture were used to study the effect of 15(S)-HETE and 15(S)-HPETE on angiogenesis. Biochemical markers of angiogenesis were analysed by ELISA. 15(S)-HETE increased vessel density in chick CAM, induced sprouting in rat aortic rings and increased endothelial cell-cell contact and formation of tubular network-like structures in HUVECs. Furthermore, it up-regulated the expression of CD31, E-selectin and vascular endothelial growth factor (VEGF) in HUVECs, indicating its pro-angiogenic effect. 15(S)-HPETE, on the other hand, decreased vessel density in chick CAM, down-regulated the expression of E-selectin (<35%), VEGF (<90%) and CD31 (<50%) and did not produce sprouting in aortic rings, suggesting an anti-angiogenic property. 15(S)-HETE-mediated up-regulation of CD 31 and VEGF was reversed by treatment with 15(S)-HPETE. These results indicate the divergent effects of hydroxy and hydroperoxy products of 15-LOX on angiogenesis, highlighting the role of these products in the co-dependence of inflammation and angiogenesis.