title: Autocrine activity of cysteinyl leukotrienes in human vascular endothelial cells: Signaling through the CysLT₂ receptor.
abstract: We evaluated the autocrine activities of cysteinyl leukotrienes (cysteinyl-LTs) in HUVEC and studied the signaling and the pharmacological profile of the CysLT2 receptor (CysLT2R) expressed by ECs, finally assessing the role of the CysLT2R in permeability alterations in a model of isolated brain. Cysteinyl-LTs and their precursor LTA4 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 CysLT2R 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 CysLT1R antagonist zafirlukast, pranlukast, pobilukast and iralukast also possess CysLT2R 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 CysLT2R in cardiovascular disease.
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy; Dipartimento di Scienze della Salute, Università degli Studi di Milano, Italy.
authors.forename: Valérie
authors.initials: V
authors.lastname: Capra
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Carnini
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Accomazzo
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Gennaro
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Fiumicelli
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Borroni
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Brivio
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Carola
authors.initials: C
authors.lastname: Buccellati
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy; Dipartimento di Medicina Clinica e Sperimentale, Università di Messina, Messina, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mangano
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Carnevali
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy. Electronic address: genrico.rovati@unimi.it.
authors.forename: Gianenrico
authors.initials: G
authors.lastname: Rovati
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy; IBIM, Consiglio Nazionale delle Ricerche, Palermo, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Sala
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D003545:Cysteine / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017572:Leukotriene A4 / Q000494:pharmacology; D017997:Leukotriene C4 / Q000494:pharmacology; D015289:Leukotrienes / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D018077:Receptors, Leukotriene / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D017572:Leukotriene A4; D015289:Leukotrienes; D018994:Myosin Light Chains; D018077:Receptors, Leukotriene; C112381:cysteinyl-leukotriene; D017997:Leukotriene C4; C412375:cysteinyl leukotriene receptor 2; D011493:Protein Kinase C; D020741:rho GTP-Binding Proteins; D003545:Cysteine; C083169:leukotriene D4 receptor
keywords: Cell contraction; CysLT(2) receptor; Cysteinyl-LTs; Transcellular biosynthesis; Vascular permeability