Retinal neovascularization is the leading cause of visual impairment in diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration. The extracellular matrix breakdown by metalloproteinase leads to vascular complications in various proliferative retinopathies. A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is involved in physiological angiogenesis. However, limited information exists regarding the role of ADAM10 in proliferative retinopathies. In this study, the levels of active ADAM10 were significantly up-regulated in the ischemic retina, and down-regulation or inactivation of ADAM10 significantly inhibited the proliferation, sprouting, migration, and tube formation of human retinal microvascular endothelial cell. Furthermore, the endothelial cell (EC)-specific deletion of ADAM10 (ADAM10