The cysteinyl leukotriene 2 receptor mediates retinal edema and pathological neovascularization in a murine model of oxygen‐induced retinopathy

• Published in: The FASEB journal 2012-03, Vol.26 (3), p.1100-1109
• Main Authors: Barajas‐Espinosa, Alma, Ni, Nathan C., Yan, Dong, Zarini, Simona, Murphy, Robert C., Funk, Colin D.
• Format: Article
• Language: English
• Subjects: Albumins - metabolism; Animals; Calcimycin - pharmacology; Calcium Ionophores - pharmacology; Capillary Permeability - drug effects; Cysteine - pharmacology; Disease Models, Animal; Endothelium, Vascular - metabolism; Gene Expression; Griffonia simplicifolia; Hydroxyeicosatetraenoic Acids - metabolism; Immunohistochemistry; inflammation; Leukotrienes - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Oxygen; Papilledema - genetics; Papilledema - metabolism; pericyte; Pericytes - metabolism; Prostaglandins - metabolism; Receptors, Leukotriene - deficiency; Receptors, Leukotriene - genetics; Retina - drug effects; Retina - metabolism; Retinal Diseases - chemically induced; Retinal Diseases - genetics; Retinal Diseases - metabolism; Retinal Neovascularization - genetics; Retinal Neovascularization - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Vascular Endothelial Growth Factor Receptor-1 - genetics; Vascular Endothelial Growth Factor Receptor-1 - metabolism
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.11-195792

Leukotrienes have been implicated in the pathogenesis of degenerative diabetic retinopathy, with research focusing primarily on leukotriene B4, with little attention devoted to the cysteinyl leukotrienes (cysLTs), which act through cysLT receptors (CysLT1R and CysLT2R). We demonstrate here the presence of CysLT2R in pericytes and endothelial cells of superficial retinal vasculature using an indirect assay by assessment of β‐galactosidase expression in CysLT2R‐knockout (KO) mice. Retinal damage was induced in KO and wild‐type (WT) mice using an established oxygen‐induced retinopathy (OIR) model. CysLT2R 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 CysLT2R in the progression of ischemic retinopathy.—Barajas‐Espinosa, A., Ni, N. C., Yan, D., Zarini, S., Murphy, R. C., Funk, C. D. The cysteinyl leukotriene 2 receptor mediates retinal edema and pathological neovascularization in a murine model of oxygen‐induced retinopathy. FASEB J. 26, 1100‐1109 (2012). www.fasebj.org