Eicosanoid regulation of angiogenesis: role of endothelial arachidonate 12-lipoxygenase

Angiogenesis, the formation of new capillaries from preexisting blood vesse ls, is a multistep, highly orchestrated process involving vessel sprouting, endothelial cell migration, proliferation, tube differentiation, and survi val. Eicosanoids, arachidonic acid (AA)-derived metabolites, have potent bi ologic activities on vascular endothelial cells. Endothelial cells can synt hesize various eicosanoids, including the 12-lipoxygenase (LOX) product 12( S)-hydroxyeicosatetraenoic acid (HETE), Here we demonstrate that endogenous 12-LOX is involved in endothelial cell angiogenic responses. First, the 12 -LOX inhibitor, N-benzyl-N-hydroxy-5-phenylpentanamide (BHPP), reduced endo thelial cell proliferation stimulated either by basic fibroblast growth fac tor (bFGF) or by vascular endothelial growth factor (VEGF), Second, 12-LOX inhibitors blocked VEGF-induced endothelial cell migration, and this blocka ge could be partially reversed by the addition of 12(S)-HETE. Third, pretre atment of an angiogenic endothelial cell line, RV-ECT, with BHPP significan tly inhibited the formation of tubelike/cordlike structures within Matrigel . Fourth, overexpression of 12-LOX in the CD4 endothelial cell line signifi cantly stimulated cell migration and tube differentiation. In agreement wit h the critical role of 12-LOX in endothelial cell angiogenic responses in v itro, the 12-LOX inhibitor BHPP significantly reduced bFGF-induced angiogen esis in vivo using a Matrigel implantation bioassay, These findings demonst rate that AA metabolism in endothelial cells, especially the 12-LOX pathway , plays a critical role in angiogenesis.(Blood .2000;95:2304-2311) (C) 2000 by The American Society of Hematology.