Resveratrol inhibits pathologic retinal neovascularization in Vldlr(-/-) mice

• Published in: Investigative ophthalmology & visual science Vol. 52; no. 5; pp. 2809 - 2816
• Main Authors: Hua, Jing, Guerin, Karen I, Chen, Jing, Michán, Shaday, Stahl, Andreas, Krah, Nathan M, Seaward, Molly R, Dennison, Roberta J, Juan, Aimee M, Hatton, Colman J, Sapieha, Przemyslaw, Sinclair, David A, Smith, Lois E H
• Format: Journal Article
• Language: English
• Published: United States Association for Research in Vision and Ophthalmology, Inc 01.04.2011
• Subjects: Administration, Oral; Angiogenesis Inhibitors - administration & dosage; Animals; Antioxidants - administration & dosage; Blotting, Western; Disease Models, Animal; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Female; Fluorescent Antibody Technique, Indirect; Glial Fibrillary Acidic Protein; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Receptors, LDL - genetics; Retina - drug effects; Retina - metabolism; Retinal Neovascularization - metabolism; Retinal Neovascularization - prevention & control; Retinal Telangiectasis - metabolism; Retinal Telangiectasis - prevention & control; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Stilbenes - administration & dosage; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1552-5783; 0146-0404; 1552-5783
• DOI: 10.1167/iovs.10-6496

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.