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Article, see p 180 Age-related macular degeneration is the leading cause of blindness in industrialized nations, affecting >10 million Americans. The most severe form of macular degeneration, the “wet” form, is caused by growth of abnormal vessels that leak excessive fluid under the retina, damaging the macula and leading to loss of sharp, central, color vision. Vascular endothelial growth factor (VEGF) is a major factor that drives vasoproliferative diseases such as macular degeneration, and antibodies to VEGF are a mainstay of treatment. In this issue of Circulation ,1 Bucher and colleagues identify tetraspanin Tspan12 as a therapeutic target for retinal vascular proliferation, and they invent a Tspan12-targeting therapy. The retinal vasculature is uniquely adapted to supply oxygen and nutrients to photoreceptor cells without blocking incoming light. However, these specialized features also make the retinal vasculature susceptible to vasoproliferative retinopathy, which is the aberrant growth of new blood vessels and breakdown of their barrier function.2 Vasoproliferative retinopathies are driven by VEGF, a key regulator of physiological and pathological angiogenesis. VEGF production is driven primarily by the hypoxia-inducible factor family of transcription factors. VEGF stimulates angiogenesis by interacting with its receptors VEGFR1 and VEGFR2, which in turn activate intracellular signaling cascades such as the Ras-mitogen-activated protein kinase pathway, triggering endothelial migration and proliferation. VEGF-induced VEGFR2 signaling also increases vascular permeability by separating VE-cadherin complexes and intercellular adhesion junctions. The most effective treatment for vasoproliferative retinopathies is anti-VEGF therapy delivered by periodic intravitreal injections. However, the lack of response in some patients and relapses of neovascularization and edema between treatments indicate the clinical need for novel treatments.2 In the current issue of Circulation , Bucher and colleagues1 discovered that tetraspanin Tspan12 is a new therapeutic target for vasoproliferative retinopathies. The tetraspanins are a superfamily of 33 integral membrane with …