title: The cysteinyl leukotriene 2 receptor mediates retinal edema and pathological neovascularization in a murine model of oxygen-induced retinopathy.
abstract: Leukotrienes have been implicated in the pathogenesis of degenerative diabetic retinopathy, with research focusing primarily on leukotriene B(4), with little attention devoted to the cysteinyl leukotrienes (cysLTs), which act through cysLT receptors (CysLT(1)R and CysLT(2)R). We demonstrate here the presence of CysLT(2)R in pericytes and endothelial cells of superficial retinal vasculature using an indirect assay by assessment of β-galactosidase expression in CysLT(2)R-knockout (KO) mice. Retinal damage was induced in KO and wild-type (WT) mice using an established oxygen-induced retinopathy (OIR) model. CysLT(2)R expression following OIR was intensely up-regulated compared to sham-treated controls. Staining with Griffonia simplicifolia lectin revealed enhanced tissue damage (as assessed by vasoobliteration/vasoproliferation) in KO mice compared to WT controls, yet the opposite was true with respect to retinal edema. However, vascular endothelial growth factor receptor 1 (VEGFR1) transcripts were increased by OIR similarly with respect to genotype. Intravitreal application of exogenous cysLTs elicited greater vasculature leakage (assessed ex vivo) in eyes from WT mice compared to KO mice. While mRNA encoding enzymes for various components of the leukotriene cascade were detected in sham- and OIR-treated retinas, only prostaglandins and hydroxyeicosatetraenoic acids, but not leukotrienes, were detected in A23187-treated retina preparations. Together, these results implicate the CysLT(2)R in the progression of ischemic retinopathy.
authors: Department of Biomedical and Molecular Sciences, Queen's University, 18 Stuart St., 433 Botterell Hall, Kingston, ON, Canada K7L 3N6.
authors: Alma
authors: A
authors: Barajas-Espinosa
authors: Nathan C
authors: NC
authors: Ni
authors: Dong
authors: D
authors: Yan
authors: Simona
authors: S
authors: Zarini
authors: Robert C
authors: RC
authors: Murphy
authors: Colin D
authors: CD
authors: Funk
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D061207:Calcium Ionophores / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D003545:Cysteine / Q000494:pharmacology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D015870:Gene Expression; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007150:Immunohistochemistry; D015289:Leukotrienes / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010100:Oxygen; D010211:Papilledema / Q000235:genetics* / Q000378:metabolism; D020286:Pericytes / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D018077:Receptors, Leukotriene / Q000172:deficiency / Q000235:genetics*; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D012164:Retinal Diseases / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D015861:Retinal Neovascularization / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000418:Albumins; D061207:Calcium Ionophores; D006893:Hydroxyeicosatetraenoic Acids; D015289:Leukotrienes; D011453:Prostaglandins; D018077:Receptors, Leukotriene; C112381:cysteinyl-leukotriene; D000001:Calcimycin; C412375:cysteinyl leukotriene receptor 2; D040281:Vascular Endothelial Growth Factor Receptor-1; D003545:Cysteine; D010100:Oxygen