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Purpose: Wet age-related macular degeneration (AMD) is characterized by choroidal neovascularization (CNV), yet current anti-VEGF therapies are ineffective in many patients. This study investigates the role of mast cell-derived granzyme B (GzmB), a serine protease responsible for the abnormal cleavage of the extracellular matrix in the outer retina. Methods: Human and mouse choroidal tissues were analyzed for mast cell distribution, GzmB expression, and age-related changes. An ex vivo choroidal sprouting assay (CSA) was used to evaluate the effects of mast cell degranulation and/or stabilization, and the pharmacologic inhibition of GzmB, using tissues from wild-type and GzmB knockout (KO) mice. Results: Aging increased mast cell accumulation and degranulation in both the human and mouse choroid, leading to elevated GzmB. GzmB KO mice exhibited reduced choroidal sprouting, and exogenous GzmB promoted angiogenesis. Both GzmB inhibition and mast cell stabilization suppressed angiogenic events, confirming GzmB's role in mast cell-driven angiogenesis. Conclusions: GzmB is a key mediator of mast cell-induced CNV. Targeting GzmB, either directly or through mast cell stabilization, offers a promising strategy for reducing angiogenesis in a condition such as wet AMD.
Uppal et al. (Mon,) studied this question.