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An Adam15 amplification loop promotes vascular endothelial growth factor-induced ocular neovascularization

Bing Xie^*,,1, Jikui Shen^,1, Aling Dong, Mara Swaim, Sean F. Hackett, Lorenza Wyder, Susanne Worpenberg, Samuel Barbieri and Peter A. Campochiaro^,2

^* Department of Ophthalmology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;

Departments of Ophthalmology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; and

Novartis Institutes for Bio-Medical Research, Expertise Platform Proteases, Basel, Switzerland

² Correspondence: Maumenee 719, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287-9277, USA. E-mail: pcampo{at}jhmi.edu

Proteins with a disintegrin and a metalloproteinase domain (ADAMs) are a family of membrane-bound proteinases that bind integrins through their disintegrin domain. In this study, we have found modest expression of ADAM15 in pericytes in normal retina and strong up-regulation of ADAM15 in retinal vascular endothelial cells in ischemic retina. Increased expression of vascular endothelial growth factor (VEGF) in the retina in the absence of ischemia also increased ADAM15 levels, and knockdown of Vegf mRNA in ischemic retina reduced Adam15 mRNA. Mice deficient in ADAM15 showed a significant reduction in ischemia-induced retinal neovascularization, choroidal neovascularization at rupture sites in Bruch’s membrane, and VEGF-induced subretinal neovascularization. ADAM15-deficient mice also showed reduced levels of VEGF₁₆₄, VEGF receptor 1, and VEGF receptor 2 in ischemic retina. These data suggest that ADAM15 and VEGF participate in an amplification loop; VEGF increases expression of ADAM15, which in turn increases expression of VEGF and its receptors. Perturbation of the loop by elimination of ADAM15 suppresses ocular neovascularization in 3 different model systems, and thus ADAM15 provides a new therapeutic target for diseases complicated by neovascularization.—Xie, B., Shen, J., Dong, A., Swaim, M., Hackett, S. F., Wyder, L., Worpenberg, S., Barbieri, S., Campochiaro, P. A. An Adam15 amplification loop promotes VEGF-induced ocular neovascularization.

Key Words: age-related macular degeneration • angiogenesis • chemokines • diabetic retinopathy • inflammation • stromal-derived factor-1 • vascular endothelial growth factor

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