Cysteinyl leukotrienes regulate endothelial cell inflammatory and proliferative signals through CysLT2 and CysLT1 receptors

Cysteinyl leukotrienes (cys-LTs), LTC4, LTD4, LTE4 are potent inflammatory lipid mediators that act through two distinct G-protein-coupled receptors, CysLT(1)R and CysLT(2)R. Although cys-LTs are shown to induce vascular leakage and atherosclerosis, the molecular mechanism by which cys-LTs modulate endothelial function is not known. Here, we show that cys-LTs (LTC4 and LTD4) induce robust calcium influx in human umbilical vein endothelial cells (HUVECs) through CysLT(2)R, but not CysLT(1)R. Further, cys-LT treatment induced endothelial cell (EC) contraction leading to monolayer disruption via CysLT(2)R/Rho kinase dependent pathway. Furthermore, stimulation with cys-LTs potentiated TNF alpha-induced VCAM-1 expression and leukocyte recruitment to ECs through CysLT(2)R. In contrast, we found that both LTC4 and LTD4 stimulated EC proliferation through CysLT(1)R. Taken together, these results suggest that cys-LTs induce endothelial inflammation and proliferation via CysLT(2)R/Rho kinase and CysLT(1)R/Erk dependent pathways, respectively, which play critical role in the etiology of cardiovascular diseases such as atherosclerosis and myocardial infarction.