Leukotriene D₄ Stimulates the Migration but Not Proliferation of Endothelial Cells Mediated by the Cysteinyl Leukotriene CysLT₁ Receptor via the Extracellular Signal-Regulated Kinase Pathway

Abstract

The actions of cysteinyl leukotrienes (CysLTs) are mediated by activating CysLT receptors, CysLT₁, and CysLT₂. The CysLT₁ receptor mediates vascular responses to CysLTs; however, its effect on the proliferation and migration of endothelial cells is not clarified. To determine this effect, we observed proliferation and migration in EA.hy926 cells, a human endothelial cell line, and the involvement of activation of mitogen-activated protein kinases (MAPKs). We found that LTD₄ did not affect the proliferation, but significantly stimulated the migration of endothelial cells. LTD₄ also induced the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, but not those of p38 or JNK. The LTD₄-induced migration and ERK1/2 phosphorylation were blocked by the CysLT₁-receptor antagonist montelukast and the dual antagonist Bay u9773, but not by the CysLT₂-receptor antagonist Bay cysLT2; the migration was also inhibited by the ERK1/2 inhibitor U0126. Our findings indicate that LTD₄ stimulates the CysLT₁ receptor–mediated migration of endothelial cells; this may be regulated by the ERK1/2 pathway.