Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness in the elderly worldwide. Wet AMD is characterized by pathologic choroidal neovascularization that invades the RPE and compromises retinal function. Although anti-vascular endothelial growth factor (anti-VEGF) therapy has been shown to improve symptoms of wet AMD in a large number of people, long-term treatment is associated with the development of geographic atrophy. The development of new therapeutic alternatives to prevent the progression of exudative AMD is still necessary. Inflammation and deterioration of the RPE are considered to be the main sources of the pathogenesis of AMD. Recent studies have reported accumulation and degranulation of mast cells in the compromised choroid of patients with AMD. When activated, mast cells can secrete a variety of biologically active mediators, including inflammatory cytokines and proteolytic enzymes such as tryptase. However, the precise role of mast cells in the pathogenesis of AMD remains largely unknown. We are interested in how mast cells participate in the initiation of inflammation in the choroid which results in pathological choroidal neovascularization. We investigated the effect of a mast cell stabilizer on angiogenic response in the choroid. The angiogenic effect of a mast cell stabilizer, ketotifen fumarate, was evaluated in laser-induced CNV model. Mice received intraperitoneal injections of ketotifen fumarate (5 and 25 mg/kg/d) or vehicle. CNV area and mononuclear phagocytes were determined respectively by using lectin staining and an anti–IBA-1 antibody on RPE/choroid flat mounts. CNV was attenuated by ketotifen fumarate with no effect on inflammatory cell recruitment. Conditioned media from activated peritoneal mast cells exerted proangiogenic effects on vascular sprouting. Tryptase increased choroidal endothelial cell migration and choroidal vascular sprouting. The study supports possible modulation of mast cells as a therapeutic modality for CNV.
