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Proangiogenic properties of 4‐hydroxy phenylretinamide (4‐HPR) in experimental neovascularization and study of its mechanisms
Author(s) -
Kannan Ram,
Sreekumar Parameswaran G,
Hinton David R
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.49.2
Subject(s) - downregulation and upregulation , neovascularization , apoptosis , choroidal neovascularization , angiogenesis , pedf , vascular endothelial growth factor , lesion , retina , thrombospondin 1 , retinal , angiopoietin , retinal pigment epithelium , endocrinology , chemistry , medicine , biology , pathology , ophthalmology , vegf receptors , biochemistry , neuroscience , gene
Purpose: We investigated the effect of 4‐HPR on a murine model of laser‐induced choroidal neovascularization (CNV). The effects of 4‐HPR on apoptosis and angiogenic factors was studied in cultured human retinal pigment epithelial cells (RPE). Methods: Retina of C57BL/6 mice was exposed to laser irradiation. 4‐HPR (0.2 mg or 1 mg) or vehicle was injected intraperitoneally daily for 14 days post‐laser. Cultured RPE were treated with 4‐HPR and apoptosis and regulation of growth factors was determined. Results: Mice treated with 4‐HPR exhibited an increase in vascular leakage, CNV lesion size, and lesion volume. A dose‐dependent decrease in lesion‐associated RPE cell number and increase in subretinal fluid was found. 4‐HPR increased RPE cytotoxicity, active caspase‐3 and apoptosis. Upregulation of vascular endothelial growth factor (VEGF)‐A, and ‐C and angiopoietin‐1 genes and increased VEGF secretion were observed with 4‐HPR (p<0.01 vs. untreated), while pigment epithelium derived growth factor and thrombospondin‐1 were significantly (p<0.05) downregulated. Conclusions: Administration of 4‐HPR to mice resulted in increased CNV. The increased neovascularization with 4‐HPR was accompanied by upregulation of proangiogenic and downregulation of antiangiogenic factors. Loss of RPE around the laser lesions may arise from 4‐HPR‐induced cell death. Supported by Arnold and Mabel Beckman Foundation.