Mast cell hyperactivity underpins the development of oxygen-induced retinopathy

Although mast cells are classically thought of as protecting the host against helminth infections and inducing allergic diseases, recent studies have revealed their additional role in neovascularization, which is critical for tissue remodeling, chronic inflammation, and carcinogenesis. Here we demonstrate that mast cells are essential for sprouting angiogenesis in oxygen-induced retinopathy (OIR). Mouse strains lacking mast cells did not develop retinal neovascularization. OIR could be induced in these mice by infusion of mast cells or by injection of mast cell tryptase (MCT). Relative hypoxia stimulated degranulation of mast cells via transient receptor potential ankyrin 1. Subsequent surges in MCT induced the production of monocyte chemotactic protein-1 (MCP1) and angiogenic factors by retinal endothelial cells leading to sprouting angiogenesis. Mast cell stabilizers, as well as specific tryptase and MCP1 inhibitors prevented the development of OIR in wild type mice. To demonstrate the relevance of these findings in humans, we also showed that preterm infants developing retinopathy of prematurity have significantly higher plasma MCT levels than age-matched controls. Our results suggest that therapies which suppress mast cell activity may have the potential for preventing eye diseases and subsequent blindness induced by neovascularization.