Autocrine activity of cysteinyl leukotrienes in human vascular endothelial cells: Signaling through the CysLT(2) receptor

We evaluated the autocrine activities of cysteinyl leukotrienes (cysteinyl-LTs) in HUVEC and studied the signaling and the pharmacological profile of the CysLT(2) receptor (CysLT(2)R) expressed by ECs, finally assessing the role of the CysLT(2)R in permeability alterations in a model of isolated brain. Cysteinyl-LTs and their precursor LTA(4) contracted HUVEC and increased permeability to macromolecules, increasing the formation of stress fibers through the phosphorylation of myosin light-chain (MLC) following Rho and PKC activation. Accordingly, in an organ model of cerebral vasculature with an intact intima, neutrophils challenge leaded to significant formation of cysteinyl-LTs and edema. Pretreatment with a selective CysLT(2)R antagonist prevented cytoskeleton rearrangement and HUVEC contraction, along with edema formation in the brain preparation, while leaving the synthesis of cysteinyl-LTs unaffected. We also demonstrate here that the CysLT(1)R antagonist zafirlukast, pranlukast, pobilukast and iralukast also possess CysLT(2)R antagonistic activity, which could help in reconsidering previous data on the role of cysteinyl-LTs in the cardiovascular system. The results obtained are further supporting a potential role for CysLT(2)R in cardiovascular disease. (C) 2015 Elsevier Inc. All rights reserved.