stilbenes and Retinal-Neovascularization

Macular telangiectasia (MacTel) is a vision-threatening retinal disease with unknown pathogenesis and no approved treatment. Very low-density lipoprotein receptor mutant mice (Vldlr(-/-)) exhibit critical features of MacTel such as retinal neovascularization and photoreceptor degeneration. In this study, the authors evaluate the therapeutic potential of resveratrol, a plant polyphenol, in Vldlr(-/-) mice as a model for MacTel.. Vldlr(-/-) and wild-type mice at postnatal day (P) 21 to P60 or P10 to P30 were treated orally with resveratrol. The number of neovascular lesions was evaluated on retinal flatmounts, and resveratrol effects on endothelial cells were assessed by Western blot for phosphorylated ERK1/2, aortic ring, and migration assays. Vegf and Gfap expression was evaluated in laser-capture microdissected retinal layers of angiogenic lesions and nonlesion areas from Vldlr(-/-) and wild-type retinas.. From P15 onward, Vldlr(-/-) retinas develop vascular lesions associated with the local upregulation of Vegf in photoreceptors and Gfap in the inner retina. Oral resveratrol reduces lesion formation when administered either before or after disease onset. The reduction of vascular lesions in resveratrol-treated Vldlr(-/-) mice is associated with the suppression of retinal Vegf transcription. Resveratrol also reduces endothelial ERK1/2 signaling as well as the migration and proliferation of endothelial cells. Furthermore, a trend toward increased rhodopsin mRNA in Vldlr(-/-) retinas is observed.. Oral administration of resveratrol is protective against retinal neovascular lesions in Vldlr(-/-) mice by inhibiting Vegf expression and angiogenic activation of retinal endothelial cells. These results suggest that resveratrol might be a safe and effective intervention for treating patients with MacTel.

Topics: Administration, Oral; Angiogenesis Inhibitors; Animals; Antioxidants; Blotting, Western; Disease Models, Animal; Endothelium, Vascular; Female; Fluorescent Antibody Technique, Indirect; Glial Fibrillary Acidic Protein; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Receptors, LDL; Resveratrol; Retina; Retinal Neovascularization; Retinal Telangiectasis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Vascular Endothelial Growth Factor A

Combretastatin A-4 (CA-4) is a vascular targeting agent known to rapidly shut off blood flow in new vessels and, as a result, regress neovascularization. In this pilot study, the ability of CA-4 to modify retinal neovascularization, which results in altered retinal vessel blood flow and retinal permeability, was evaluated in aphakic long-term galactose-fed beagles, an animal model that develops diabetes-like retinal neovascularization.. Two (2) groups of aphakic dogs, each group comprised of 4 galactose-fed dogs and 2 age-matched controls dogs, were utilized. Each group initially received the combretastatin A-4-phosphate prodrug (CA-4P) as either sub-Tenon's injections, administered at the corneoscleral junction, or intravitreal injections. Six (6) weeks after this treatment, all dogs also received systemic (intravenous) injections of CA-4P. Retinal vascular changes were monitored at 2-week intervals by fluorescein angiography.. All galactose-fed dogs demonstrated the presence of retinal neovascular lesions by fluorescein angiograms. Fluorescein leakage or perfusion through neovascular vessels was not altered by either sub-Tenon's, intravitreal, or systemic CA-4P administration. Whereas CA-4P was well tolerated by the healthy eyes of the control animals, its administration to some galactose-fed dogs was associated with corneal edema and increases in intraocular pressure following sub-Tenon's and intraocular injections.. Neovascularization in the galactose-fed dog progresses over a period of years, similar to that observed with clinical diabetic retinopathy. The failure of CA-4P to ameliorate neovascularization suggests that chronic, long-term administration may be required to destroy the slowly growing retinal endothelial cells.

Topics: Animals; Antineoplastic Agents, Phytogenic; Aphakia; Diabetic Retinopathy; Disease Models, Animal; Dogs; Fluorescein Angiography; Galactose; Injections; Intraocular Pressure; Prodrugs; Retinal Neovascularization; Retinal Vessels; Stilbenes